1 5071164742194692183 PDF

European Journal of Applied Physiology
https://doi.org/10.1007/s00421-020-04360-2
INVITED REVIEW
The impact of statins on physical activity and exercise capacity:

an overview of the evidence, mechanisms, and recommendations
Allyson M. Schweitzer1 · Molly A. Gingrich1 · Thomas J. Hawke1 · Irena A. Rebalka1
Received: 22 December 2019 / Accepted: 24 March 2020

© Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract
Purpose Statins are among the most widely prescribed medications worldwide. Considered the ‘gold-standard’ treatment
for cardiovascular disease (CVD), statins inhibit HMG-CoA reductase to ultimately reduce serum LDL-cholesterol lev-
els. Unfortunately, the main adverse event of statin use is the development of muscle-associated problems, referred to as
SAMS (statin-associated muscle symptoms). While regular moderate physical activity also decreases CVD risk, there is
apprehension that physical activity may induce and/or exacerbate SAMS. While much work has gone into identifying the
epidemiology of SAMS, only recent research has focused on the extent to which these muscle symptoms are accompanied
by functional declines. The purpose of this review is to provide an overview of possible mechanisms underlying SAMS and
summarize current evidence regarding the relationship between statin treatment, physical activity, exercise capacity, and
SAMS development.
Methods PubMed and Google Scholar databases were used to search the most relevant and up-to-date peer-reviewed research
on the topic.
Results The mechanism(s) behind SAMS, including altered mitochondrial metabolism, reduced coenzyme Q10 levels,
reduced vitamin D levels, impaired calcium homeostasis, elevated extracellular glutamate, and genetic polymorphisms, still
lack consensus and remain up for debate. Our summation of the evidence leads us to suggest that the etiology of SAMS
development is likely multifactorial. Our review also demonstrates that there is limited evidence for statins impairing exercise
adaptations or reducing exercise capacity for the majority of the investigated populations.
Conclusion The available evidence indicates that the benefits of engaging in physical activity while on statin medication
largely outweigh the risks.
Keywords Statins · Exercise · HMG CoA reductase inhibitor · Cardiovascular disease · Myalgia · Myopathy · SAMS ·
Stain-induced muscle symptoms
Abbreviations CVD Cardiovascular disease

ADP Adenosine diphosphate ETC Electron transport chain
ATP Adenosine triphosphate HIV Human immunodeficiency virus
BMI Body mass index HMG-CoA 3-Hydroxy-3-methylglutaryl coenzyme A
CK Creatine kinase LDL-C Low-density lipoprotein cholesterol
CoQ10 Co-enzyme Q10 mPTP Mitochondrial permeability transition pore
CRF Cardiorespiratory fitness O2− Superoxide
CSEP Canadian Society for Exercise Physiology PGC-1α Peroxisome proliferator-activated receptor
gamma coactivator 1-alpha
ROS Reactive oxygen species
Communicated by Michael Lindinger. SAMS Statin-associated muscle symptoms
SERCA Sarco-endoplasmic reticulum calcium
* Thomas J. Hawke
[email protected] ATPase
SNPs Single nucleotide polymorphisms
1
Department of Pathology and Molecular Medicine, 4N65
Health Sciences Centre, McMaster University, 1200 Main
Street West, Hamilton, ON L8N 3Z5, Canada
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Vol.:(0123456789)
Introduction soreness, weakness, cramps, and aches in the upper and/

or lower extremities. Given that regular physical activ-
Cardiovascular disease (CVD) is the number one cause ity significantly reduces the risk of CVD development,
of death worldwide (Benjamin et al. 2019). As a chronic progression, and mortality (Artinian et al 2010; Oja et al.
illness, CVD develops gradually over the lifespan, and 2017; Paffenbarger, Blair and Lee 2001; Sharman, La
symptoms often manifest into a diagnosis around mid- Gerche and Coombes 2015; Thompson et al. 2003), it is
dle age. Given this typically slow progression, risk factor also a concern to note that exercise may induce and/or
identification and modification have become a key aspect exacerbate SAMS (Bruckert et al. 2005; Thompson et al.
of disease prevention. Lifestyle modifications such as con- 1997). In fact, statin prescription is widely associated with
suming a healthy diet and participating in regular physi- a reduction in physical activity levels, with similar con-
cal activity are two well-defined and modifiable factors clusions drawn by 3 large observational studies (Lee et al.
that greatly reduce one’s risk of cardiovascular mortality 2014; Loenneke and Loprinzi 2018; Scott et al. 2009).
(Artinian et al. 2010; Kubota et al. 2017). In addition to Whether this reduction in physical activity is directly or
these lifestyle modifications, prescription pharmaceuticals indirectly associated with statin use, however, is unclear.
have been demonstrated to reduce cardiovascular-related Overall, statin users were found to perform less moder-
mortality. The most commonly prescribed class of phar- ate and vigorous physical activity compared to non-users,
maceuticals for the primary and secondary prevention of had increased sedentary behaviour, averaged significantly
CVD are the 3-hydroxy-3-methylglutaryl coenzyme A fewer steps per day than non-users, and had reduced odds
(HMG-CoA) reductase inhibitors, collectively referred to of engaging in muscle-strengthening activities. Overall,
as statins (Hennessy et al. 2016; Pencina et al. 2014). the aforementioned muscle-associated complications are
The role of statins in CVD prevention centers on their the predominant reason for whole-class statin non-compli-
ability to reduce total systemic cholesterol circulation. ance (Cohen et al. 2012; Colivicchi et al. 2007; McGinnis
Statins are competitive inhibitors of HMG-CoA reduc- et al. 2007; Zhang, Plutzky and Turchin 2013), highlight-
tase, a key rate-limiting enzyme in the synthesis of the ing a major clinical obstacle in the reduction of CVD risk.
cholesterol precursor molecule mevalonate (Schachter Despite its clinical relevance, the underlying
2005; Ward et al. 2019). Additionally, statin therapy has mechanism(s) of SAMS are inconclusive, and there is a
been demonstrated to upregulate low-density lipopro- lack of consensus on the combined benefits of statins and
tein cholesterol (LDL-C) receptors in peripheral tissues, physical activity; both individually highlighted to profoundly
further lowering total cholesterol circulation (Istvan and reduce CVD risk. This review aims to summarize the most
Deisenhofer 2001). The effects of statin therapy on LDL-C prominent hypothesized mechanisms of statin-induced alter-
reduction and subsequent decreases in CVD-associated ations to skeletal muscle metabolism and their subsequent
mortalities have been widely demonstrated (Downs et al. implications on SAMS. The effect of statins on aerobic and
1998; Yusuf et al. 2016; Pedersen et al. 2004; Zhou and anaerobic training capacity will also be examined. Lastly,
Liao 2010). The efficacy of statin therapy noted in these the safety of physical activity and statin co-prescription
clinical trials has led to widespread statin prescriptions, in both the general population of statin users and those at
with approximately 1 in 4 North American adults being higher risk of SAMS will be evaluated.
recommended statin therapy (Gu et al. 2014; Hennessy
et al. 2016; Pencina et al. 2014).
Though generally well tolerated, up to 29% of statin Proposed mechanisms for SAMS
users develop statin-associated muscle symptoms (SAMS)
(Fernandez et al. 2011; Sathasivam and Lecky 2008), While a number of statin-induced alterations to skeletal
including muscle pain (myalgia), inflammation (myositis), muscle metabolism have been proposed, a collective, con-
damage (myopathy), and in extreme cases, rhabdomyolysis clusive, mechanistic origin for all SAMS remains elusive.
(Bruckert et al. 2005; El-Salem et al. 2011; Pasternak et al. Below are several of the most prominent proposed mecha-
2002; Thompson et al. 2016). Despite reports implicating nisms explaining the etiology of SAMS: altered mitochon-
the ‘nocebo effect’ in many SAMS cases (Finegold et al. drial metabolism, reduced coenzyme Q10 levels, reduced
2014; Gupta et al. 2017), the cessation of these symp- vitamin D levels, disrupted calcium homeostasis, disrupted
toms is often only achieved through statin discontinuation glutamate homeostasis, and genetic single nucleotide poly-
(Cohen et al. 2012; Colivicchi et al. 2007). Of the SAMS, morphisms (SNPs) (Fig. 1).
myalgia is by far the most common complaint (Ramkumar,
Raghunath and Raghunath 2016), presenting as muscle
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Fig. 1 Schematic of the proposed statin-induced alterations to skel- bility of statin users’ myofibers. References supporting each mecha-
etal muscle and vasculature in relation to SAMS, as discussed in this nism correspond to the superscript numbers within the figure and are
review. Statins enter the circulation and reduce serum coenzyme Q10 detailed below. 1, Banach et al. (2015), Berthold et al. (2006), Mar-
and vitamin D concentrations. It is unclear whether these reductions coff and Thompson (2007), McMurray et al. (2010), Morrison et al.
in serum levels result in reduced intramuscular levels. Statins have (2016), Taylor et al. 2015); Qu et al. (2018). 2, Eisen et al. (2014),
been demonstrated to increase ROS production as well as decrease Khayznikov et al. (2015), Kurnik et al. (2012), Michalska-Kasiczak
mitochondrial respiration and ATP production within the myofiber. et al. (2015), Parker et al. (2013), Riphagen et al. (2012), Wu et al.
An increased antioxidant demand as a result of statin treatment has (2018). 3, Camerino et al. (2017). 4, Busanello et al. (2018), du
been demonstrated to increase xCT transporter content/activity as Souich et al. 2017). 5, Allard et al. (2018), Bouitbir et al. (2016),
well as increase concentrations of extracellular glutamate. SERCA Busanello et al. (2017), Davies et al. (1982), Pryor (1982), Rebalka
activity has been demonstrated to increase in asymptomatic but not et al. (2019). 6, Allard et al. (2018), Bouitbir et al. 2016, Busanello
symptomatic statin users compared to non-users and may contribute et al. (2017), Davies et al. (1982), Dohlmann et al. (2019), Pryor
to the impaired calcium homeostasis demonstrated in statin users. (1982), Rebalka et al. (2019). 7, Allard et al. (2018). 8, Camerino
CLC-1 chloride channel content has been demonstrated to be reduced et al. (2017). 9, Rebalka et al. (2019)
in statin users and has been implicated to reduce the membrane sta-
Mitochondrial metabolism et al. 2000; Sena and Chandel 2012); however, when there is
imbalance, excess ROS generates oxidative stress and dam-
The mitochondria are the primary source of energy in ani- age within the cell. The most common free radical produced
mal cells that undergo aerobic metabolism (Dykens and Will by the ETC is superoxide ( O2−) (Brand 2010). The unpaired
2008). This energy, in the form of adenosine triphosphate electron present on each O2− moiety is able to readily accept
(ATP), is integral for numerous cell processes including electrons from surrounding proteins, subsequently oxidizing
membrane transport, cell signaling, and, specific to mus- and altering their function and activity.
cle, contraction. As they are extremely metabolically active, Endogenous and exogenous antioxidants act to will-
mature skeletal muscle cells (myofibers) require large, con- ingly donate their electrons to ROS to reduce the poten-
tinuous supplies of ATP to survive and are host to an abun- tial for oxidative cellular damage. Antioxidant homeosta-
dance of mitochondria. Mitochondria create ATP through sis can become disrupted, however, during exceptional
oxidative phosphorylation via the electron transport chain circumstances such as physical activity or in response to
(ETC), a series of electron-transferring complexes located xenobiotics; synthetic chemicals that are not produced
on the inner mitochondrial membrane. This transfer of by the body including statins and zidovudine (Dykens
electrons creates an electrical gradient whose energy is har- and Will 2008; Kline et al. 2009). Statins in particular
nessed to combine adenosine diphosphate (ADP) with an have been demonstrated to reduce mitochondrial respi-
inorganic phosphate to create ATP. ration and increase ROS production (Allard et al. 2018;
One consequence of ETC activity is the production of Bouitbir et al. 2016; Busanello et al. 2017; Davies et al.
free radicals, referred to as reactive oxygen species (ROS). 1982; Pryor 1982; Rebalka et al. 2019). Allard et al.
In modest amounts, ROS play an important role in many (2018) demonstrated that muscle from symptomatic sta-
cellular processes including myofiber repair (Branch 1998; tin users had reductions in complex II and IV activity and
Hamanaka and Chandel 2010; Nunes-Silva et al. 2014; Rhee an approximate 28% decrease in ATP production capacity
13
compared to muscle from non-statin users. Additionally, oxidation rates and increase ROS production. The authors
Dohlmann et al. (2019) demonstrated reduced complex II also suggest that these alterations are highly calcium
respiration in both symptomatic and asymptomatic statin dependent, may indirectly affect the skeletal muscle, and
users. When ETC respiration capacity was normalized may contribute to the toxicity demonstrated with statin
to mitochondrial content, respiratory capacity was also treatment.
reduced in both symptomatic and asymptomatic statin Evidence within the literature supports that statin use
users (Busanello et al. 2017). Reduced mitochondrial res- increases mitochondrial-mediated oxidative stress through
piration rates can cause electrons to leak from the ETC reduced mitochondrial respiration. Whether these alterations
(Hamanaka and Chandel 2010; Panajatovic et al. 2019), affect functional measures is discussed below. Given that not
thereby reducing the electrical gradient and subsequent all statin-users suffer from SAMS, there are likely additional
ATP production. If the myofiber is consistently unable to contributing factors in excess of alterations to mitochondrial
meet its energy requirements, apoptotic pathways may be capacity that predispose one to their development. Some of
initiated. This concept is a proposed mechanism of statin- these additional factors are proposed below.
induced myofiber death. Additionally, electrons that leak
from the ETC promptly react in the oxygen-rich surround- Coenzyme Q10
ings to form O2− and increase ROS production. Given that
exercise increases mitochondrial ROS production, if ROS Co-enzyme Q10 (CoQ10) is a fat-soluble, vitamin-like sub-
is a contributor to SAMS, it is of concern that exercise stance that is ubiquitously expressed throughout the human
may exacerbate or induce these symptoms. This concern body (James et al. 2004). When reduced to ubiquinol, it pro-
is addressed in further detail below. tects cells against free radical-facilitated oxidative stress and
Contrasting the increased ROS production, exercise also is a cofactor for ETC electron transfer (James et al. 2004).
evokes a number of mitochondrial adaptions that posi- It has been widely reported that statin users have reduced
tively affect the muscle’s response to statins. One of these plasma CoQ10 levels (Banach et al. 2015; Berthold et al.
adaptations is the upregulation of peroxisome proliferator- 2006; Marcoff and Thompson 2007; McMurray et al. 2010;
activated receptor gamma coactivator 1-alpha (PGC-1α) Morrison et al. 2016; Taylor et al. 2015; Qu et al. 2018).
activity, the primary regulator of mitochondrial biogenesis This can be attributed to the attenuation of mevalonate pro-
that has recently been implicated to mitigate the effects of duction via statin use, subsequently attenuating farnesyl
statin myotoxicity on mitochondrial health. In a murine pyrophosphate and CoQ10 production (James et al. 2004).
model, Panajatovic et al. (2019) demonstrate that skeletal Additionally, as CoQ10 is systemically transported in con-
muscle overexpression of PGC-1α protects against statin- junction with LDL, statin-induced reductions in total LDL
induced mitochondrial alterations and rescues functional content may also reduce systemic CoQ10 transport (James
measures such as reduced distance run to exhaustion. et al. 2004). Due to its roles within the mitochondria, it was
PGC-1α has been shown to regulate the expression of hypothesized that this lack of CoQ10 may be contributing
several endogenous antioxidant proteins and reduce ROS to the reduced respiration and increased ROS production
production, lending cause to its positive effects on mito- demonstrated in the mitochondria of statin users.
chondrial health when overexpressed (Baar et al. 2002; Unsurprisingly, CoQ10 supplementation has been pro-
St-Pierre et al. 2003). Additionally, Zoladz et al. (2016) posed as a treatment for SAMS. Recent literature, however,
assessed mitochondrial bioenergetics in rats following 8 demonstrated that while CoQ10 supplementation effectively
weeks of endurance training. Interestingly, the authors increased serum CoQ10 levels, SAMS developed at the same
present that ROS production is reduced in active muscle rate with and without supplementation (Banach et al. 2015;
and increased in resting muscle following endurance train- Bogsrud et al. 2013; Bookstaver et al. 2012; Rott et al. 2016;
ing. The authors suggest that these changes may contribute Taylor et al. 2015; Young et al. 2007). This lack of symptom
to increased mitochondria efficiency in active muscle, as relief may be explained by the absence of change in intra-
well as signal for muscle remodeling and enhance mito- muscular CoQ10 levels. Though serum CoQ10 levels are
chondrial function in resting muscle. While this preclinical reduced in statin users, evidence does not support its reduced
evidence demonstrates a therapeutic role of exercise on presence in the muscle (Busanello et al. 2017; Camerino
SAMS, more research is required before definitive conclu- et al. 2017), making its contribution to SAMS questionable.
sions can be drawn in humans. As previously mentioned, SAMS manifestation may be mul-
In addition to skeletal muscle mitochondria, statins tifactorial and thus it is unlikely that CoQ10 disruption alone
have also been demonstrated to alter the metabolism of is the underlying cause of SAMS development.
mitochondria in the vascular endothelium (Broniarek and
Jarmuszkiewicz 2018). Atorvastatin treatment in vitro
was demonstrated to decrease endothelial mitochondrial
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Vitamin D Interestingly, when SERCA activity was assessed in statin

users, activity was 30% higher in asymptomatic users com-
Vitamin D is a fat-soluble vitamin that is well known for pared to non-users, but no difference was observed between
facilitating calcium uptake into bones. In addition to its symptomatic statin users and non-users (Allard et al. 2018).
role in maintaining bone health, vitamin D has been dem- Past research has demonstrated that simvastatin increases
onstrated to have an important role in muscle health. Vita- release of calcium from the mitochondrial permeability
min D deficiency has been associated with proximal muscle transition pore (mPTP) (du Souich et al. 2017), thus, the
weakness and myopathy and has been demonstrated to play increase in SERCA activity demonstrated in asymptomatic
a role in intracellular myofiber calcium homeostasis (Caruso users may be the compensatory result of this increased sar-
and Fuzaylov 2013; Girgis et al. 2013; Glerup et al. 2000; coplasm concentration and, in line with this hypothesis,
Rasheed et al. 2013). Furthermore, vitamin D has been dem- statin users who are not able to compensate may develop
onstrated to enhance the hepatic and intestinal production SAMS. Alternatively, increased SERCA activity may impair
of cytochrome P450 3A4, a key enzyme in statin metabo- calcium homeostasis rather than be a compensatory mecha-
lism (Lynch and Price 2007; Wang et al. 2013). Accord- nism. SERCA content has been demonstrated to decrease
ingly, reduced vitamin D levels can reduce statin metabolism in human skeletal muscle following 5 weeks of endurance
and clearance, resulting in a greater chance for myotoxicity training; an adaptation that is largely responsible for improv-
(Ahmed et al. 2009; Glueck et al. 2011a, b; Glueck et al. ing muscular mechanical efficiency (Majerczak et al. 2008).
2011a, b; Pérez-Castrillón et al. 2010). If increased SERCA activity does contribute to the impaired
A meta-analysis investigating the association between calcium handling demonstrated in statin users, the findings
vitamin D and SAMS found that statin users with SAMS of Majerczak et al. (2008) suggest that physical activity may
had significantly lower plasma vitamin D levels than asymp- benefit these individuals.
tomatic statin users (Michalska-Kasiczak et al. 2015). In In addition, statin users with SAMS demonstrate a
contrast, however, several studies report no significant 40% reduction in CLC-1 chloride channel proteins when
differences in vitamin D levels between symptomatic and compared to non-statin users (Camerino et al. 2017). This
asymptomatic statin users or no increases in SAMS with channel is responsible for resting sarcolemma membrane
vitamin D deficiency (Eisen et al. 2014; Kurnik et al. 2012; stability, and thus reductions may lead to membrane hyper-
Parker et al. 2013; Riphagen et al. 2012). Wu et al. (2018) excitability, and a decreased threshold for subsequent mus-
tested the effects of vitamin D supplementation on statin cle cramping, spasm, and weakness (Camerino et al. 2017;
adherence and found no effect over a 24-month period, while Jurkat-Rott and Lehmann-Horn 2005). This theory also sug-
Khayznikov et al. (2015) found previously statin-intolerant gests that since membranes are hyperexcitable, the rate of
patients to be free of SAMS after 24 months of vitamin force production in statin users may also be greater. Allard
D supplementation. Overall, while statins seem to reduce et al. (2018) recently demonstrated that the median current
serum vitamin D levels, the muscle-specific role of vitamin needed for statin users to produce 30% of their maximal
D in SAMS is largely unknown. voluntary contraction was 16% lower than non-statin users;
however, the maximal rate of force development did not dif-
Calcium homeostasis fer between groups. Morville et al. (2019) similarly demon-
strated no differences in rate of force development between
Calcium, through its reversible binding with thin-filament statin users (asymptomatic or symptomatic) and non-users.
troponin, plays an essential role in both skeletal muscle con- Furthermore, Mallinson et al. (2015) demonstrated that
traction and relaxation. Due to these roles, calcium is also though maximal force did not differ between statin users and
a viable factor involved in producing SAMS, which include non-users, statin users took longer to reach this maximum.
muscle spasms and cramping. Taken together, these results suggest that if a difference in
Calcium’s re-uptake into the sarcoplasmic reticulum membrane excitability does exist between statin users and
offers a mechanism for spasm and cramping. If calcium non-users, other mechanisms might impair contractility
remains in high concentrations within the sarcoplasm, cross- resulting in no functional differences.
bridge cycling and muscle contraction will persist (Berchtold When assessed from a functional level, Allard et al.
et al. 2000; Ebashi and Endo 1968; Gollnick et al. 1991). (2018) demonstrated that time to relaxation following a
The primary pump responsible for calcium reuptake into the single muscle contraction was lower in asymptomatic and
sarcoplasmic reticulum is sarco-endoplasmic reticulum cal- symptomatic statin users than non-users, counterintuitive
cium ATPase (SERCA) (MacLennan et al. 1985). Camerino to what the aforementioned SERCA activity data would
et al. (2017) found no difference in SERCA gene expres- suggest. Following continuous contraction, however, statin
sion between statin users and non-statin users; however, users’ muscles took longer to relax and the rate of force
the activity of SERCA in this study was not investigated. development deceased more rapidly with each consecutive
13
contraction (Allard et al. 2018). This largely suggests that to play a role in cancer-induced bone pain (Ungard, Seidlitz
calcium homeostatic mechanisms may be altered in statin and Singh 2014). Reinforcing the role of glutamate in noci-
users as a whole, but that elevated SERCA activity in asymp- ception, intramuscular injections of glutamate elicit experi-
tomatic statin users is insufficient to alter muscle kinetics. mental induction of muscle pain (Cairns et al. 2001, 2003;
Though the specifics of this mechanism require further Svensson et al. 2005), and elevations in the presence of
investigation, evidence supports that statins alter calcium extracellular glutamate have been found in individuals with
homeostasis, which likely has an effect on the myofiber. chronic myalgia and pain conditions (Rosendal et al. 2004;
These effects could be direct (alterations to calcium release/ Sarchielli et al. 2007). Furthermore, chronic high levels of
reuptake) or indirect (downstream effects on the mitochon- extracellular glutamate can sensitize nociceptors, lowering
dria and ATP production). It has been suggested that statins their threshold for activation, a process termed long-term
alter mPTP permeability and increase mitochondrial calcium potentiation. Glutamate is implicated to cause long-term
uptake (Busanello et al. 2018). If enough calcium is taken up potentiation in pathologies such as fibromyalgia and chronic
by the mitochondria, respiration is impeded, swelling may pain (Sarchielli et al. 2007).
occur, and apoptotic/necrotic pathways may be initiated Rebalka et al. (2019) demonstrated an increase in system
(Busanello et al. 2018; Marchi et al. 2018; Orrenius et al. X−c transporter content and extracellular glutamate follow-
2003; Pinton et al. 2008). This could explain the deficits ing statin treatment in vitro. The release of glutamate from
in mitochondrial respiration demonstrated in statin users as skeletal muscle cells was independent of muscle cell damage
well as the reduction in ATP production capacity. In sup- and positively correlated to the concentration and duration of
port of this concept, Busanello et al. (2018) showed that statin administration. This observation was specific to skel-
blocking the mPTP in statin-treated mice restored normal etal muscle cells, and similar observations were not observed
mitochondrial respiration. in dermal fibroblasts, consistent with the clinical observa-
In conclusion, while there appears to be a role for cal- tion that statin users do not report dermal pain as a side
cium homeostasis in SAMS, identification of the direct and/ effect of statin prescription. Furthermore, when system X−c
or indirect mechanism requires further elucidation. As not activity was blocked, statin treatment did not cause increases
all statin users develop SAMS, a predisposing factor likely in extracellular glutamate content. It was hypothesized that
needs to be present for SAMS to arise. This could be a previ- increased system X −c activity was necessary to compensate
ously manifested reduced calcium handling capacity, or any for the statin-induced increases in ROS production. Given
other factor exacerbated by reduced calcium homeostasis that cysteine is required for glutathione synthesis and can-
including poor mitochondrial function or impaired antioxi- not be synthesized within the myofiber, it must be imported
dant capacity. from extracellular sources. As such, system X−c is upregu-
lated to increase cystine influx, conversion to cysteine, and
Glutamate subsequent glutathione synthesis. A consequence of the
increased intracellular cysteine is an increase in extracel-
Glutamate is the most abundant excitatory neurotransmit- lular glutamate, demonstrated to cause pain perception and/
ter in the central nervous system and acts as an activator of or long-term potentiation (Rosendal et al. 2004; Sarchielli
both central and peripheral nociceptors. It is also a metaboli- et al. 2007). Importantly, the aforementioned pathway offers
cally active amino acid in skeletal muscle that is involved a mechanism for pain in the absence of damage, which is
in antioxidant creation and energy metabolism. The distinct often the case with statin-induced muscle pain. While clini-
compartmental functions of glutamate make it a very tightly cal evidence supports glutamate as a general instigator of
regulated metabolite. To avoid nociceptor overexcitation, pain, follow-up studies are needed to elucidate whether this
glutamate has a low interstitial concentration relative to mechanism translates in vivo for SAMS.
inside the cell, including muscle cells specifically (Essen-
Gustavsson and Blomstrand 2002; Gerdle et al. 2016; Gra- SLCO1B1 single nucleotide polymorphism
ham et al. 2000; Hu et al. 1994; Newsholme et al. 2003;
Pinky et al. 2018). In fact, glutamate has the greatest skeletal Properties of xenobiotics including their lipophilicity, half-
muscle intracellular-to-plasma gradient in the human body life, and clearance/metabolism play a role in their toxic-
(Bergstrom et al. 1974). ity. SAMS are more likely to occur when taking lipophilic
Two distinct transporters have been identified on skeletal statins, which do not require active transport to cross cell
muscle for glutamate transport. System X−ag is responsible membranes (Bruckert et al. 2005; Dale et al. 2007). This
for glutamate uptake and system X −c, a cystine-glutamate allows lipophilic statins to freely increase both their concen-
antiporter, is responsible for glutamate extrusion (Rutten tration within the myofiber and their potential for myotoxic-
et al. 2005). Increases in extracellular glutamate through ity (du Souich et al. 2017; Ward et al. 2019). Furthermore,
upregulation of system X −c activity have been demonstrated lipophilic statins are less readily excreted through the renal
13
system which increases their time in circulation (Ward et al. the ubiquitin proteasome pathway, protein folding, catabo-
2019). This is troublesome, as the longer a statin is in circu- lism, and apoptosis, suggesting that statins may disrupt the
lation, the more likely it is to have toxic effects on peripheral balance between degradation and repair following myofiber
tissues (Mancini et al. 2011). injury (Urso et al. 2005). While no clinical studies directly
All statins go through first-pass clearance in the gut and assess muscle repair in statin users following exercise, stud-
are metabolized in the liver. The OATP1B1 transporter ies have assessed their serum creatine kinase (CK) levels
exists on hepatic cells and is responsible for the influx of (Allard et al. 2018; Bouitbir et al. 2016; Morville et al. 2019;
xenobiotics (MoBhammer et al. 2014; Romaine et al. 2010). Parker et al. 2013). Upon sarcolemma damage/disruption,
Importantly, a SNP on the SLCO1B1 gene that encodes this CK is released from the myofiber, and is, therefore, often
transporter has been positively correlated with SAMS preva- used as a clinical marker to indicate skeletal muscle damage
lence (Brunham et al. 2012; Carr et al. 2019; DeGorter et al. (Ganga, Slim and Thompson 2014). Intuitively, it is common
2013; Donnelly et al. 2011; Niemi et al. 2004; Niemi 2010; for CK to be elevated following strenuous exercise (Parker
Santos et al. 2012). This SNP has been indicated to create a et al. 2012). Compared to non-users, Parker et al. (2013) and
less functional OATP1B1 transporter and thus reduces the Bouitbir et al. (2016) found statin users to have elevated CK
hepatic influx of xenobiotics, including statins (Meyer du levels at rest, indicating a greater baseline level of muscle
Schwabedissen et al. 2015). This transporter exists on the damage. A recent case study also describes the development
liver but not the muscle, and thus muscle influx of xeno- of acute rhabdomyolysis in a marathon runner treated with
biotics is unaffected by this SNP (du Souich et al. 2017). rosuvastatin, characterized by severe pain and elevated CK
While Hubáček et al. (2015) found no association between levels (Toussirot et al. 2015). It is important to note, how-
myalgia and the SLCO1B1 variant in a Czech population, ever, that isolated case studies are ineffective in implicat-
these participants were on low-dose simvastatin or atorvas- ing statins, as an entire class of pharmaceuticals, in causing
tatin, indicating that dose and statin type may play a role in rhabdomyolysis. Similarly, a group of statin-treated amateur
this association. These results follow the trends of the previ- runners had greater increases to serum CK than their statin-
ous sections, suggesting that this SNP may contribute to the naïve peers after completing the Boston Marathon (Parker
development of SAMS, but in isolation is likely insufficient. et al. 2012). In this case, increasing age was associated with
higher serum CK levels.
Concluding remarks on the proposed mechanisms As these aforementioned studies do not directly assess the
of SAMS impact of statins on tissue repair, preclinical models must be
assessed to draw preliminary conclusions. Two recent stud-
Overall, the literature implicates numerous mechanisms to ies found statin-treated animals to have impaired myofiber
be involved in SAMS, the list of which was not exhausted regeneration (Otrocka-Domagala and Paździor-Czapula
in this review (see the following reviews for further read- 2018; Rebalka et al. 2017). Rebalka et al. (2017) found that,
ing: Bouitbir et al. 2019; Gluba-Brzozka et al. 2016). SAMS following cardiotoxin injection and myofiber lysis, myofiber
likely present due to a concurrent combination of multiple area was significantly reduced in mice treated with statins
mechanisms. This would explain why altering a single vari- when compared to their statin-naïve counterparts ten days
able, as conducted by many of the studies detailed above, is post-injury. As a time-course experiment was not completed,
inadequate to significantly and reproducibly treat SAMS. it is not clear if statin-treated muscle regenerated completely.
Future comprehensive studies are needed to identify which Complementing this work, Otrocka-Domagala and Paździor-
of the aforementioned variables play a greater contributing Czapula (2018) saw similar findings in a statin-treated por-
role in the etiology of SAMS. cine model. After causing muscle necrosis, the inflammatory
response (particularly M1 macrophage activation), demon-
strated by a prolonged presence and degree of inflammation,
Effects of statins on muscle regeneration was delayed in statin-treated animals. Similar to Rebalka
et al. (2017), this study did not demonstrate whether repair
Statins have been demonstrated to alter the ultrastructure was delayed or completely impeded. A study by Trapani
of skeletal muscle as well as its metabolism (Allard et al. et al. (2012) looked later in the time course of muscle repair
2018; Busanello et al. 2018; Camerino et al. 2017; Rebalka in the presence of statin treatment. 21 days following muscle
et al. 2019). As such, concern arises surrounding muscle injury, histology revealed completely restored tibialis ante-
regeneration in statin users; most notably exercise-induced rior muscle architecture in the absence of statin treatment.
myofiber injury. Simvastatin treated mice, however, still displayed central
Following eccentrically induced muscle damage, Urso nucleation. Importantly, mevalonate co-therapy negated the
et al. (2005) found significant alterations to gene expression effect of statin treatment, abrogating the presence of central
in statin users. Many of these altered genes were involved in nuclei and supporting that the observed regenerative delay
13
was a result of reduced cholesterol biosynthesis pathway an alternative to regular physical activity, statins are extremely
entities (Trapani et al. 2012). effective in both primary and secondary CVD prevention. As
Another indication of the effect of statins on muscle repair both statins and aerobic physical activity have compelling evi-
can be drawn from in vitro work. Satellite cells, activated dence in support of their benefits for cardiovascular health, it
in response to myofiber injury, proliferate and differentiate has been suggested that combination therapy of the two may
into myoblasts to facilitate tissue repair (Hawke and Garry provide additive effects. Concerns arise, however, given that
2001). Geranylgeraniol, downstream of mevalonate in the the predominant negative side effects of statin use are skel-
cholesterol biosynthesis pathway, has been shown to induce etal muscle related. As physical activity stresses the muscu-
myogenic differentiation of murine myoblasts derived from loskeletal system, there is apprehension that the double-hit of
muscle satellite cells and reduce statin-induced muscle cell statins plus exercise may increase the risk of adverse events.
damage (Cao et al. 2009; Matsubara et al. 2018). Similarly, The following information aims to consolidate the current
statin treatment has been shown to affect satellite cell dif- evidence for an effect of statins on aerobic fitness capacity and
ferentiation and reduce myoblast fusion, attenuating the pro- metabolism and to determine whether aerobic physical activ-
duction of multinucleated entities (Baba et al. 2008; Martini ity should be prescribed in combination with statin therapy.
et al. 2009; Trapani et al. 2012). These impairments were See Table 1 for a summary of this evidence.
rescued with mevalonate co-treatment, validating the impor- To begin, evidence supporting the danger of combina-
tance of downstream products of the cholesterol biosynthe- tion physical activity and statin treatment must be exam-
sis pathway in muscle maturation (Trapani et al. 2012). As ined. A 2005 study by Bruckert et al. is commonly cited as
satellite cells are primary mediators of muscle regeneration, evidence that SAMS are aggravated by physical activity. In
these results are indeed concerning for muscle repair and this study, 40% of the population reporting myalgia indicated
regeneration in the presence of statin therapy. that certain factors triggered their symptoms. Of this 40%,
Exercise has many positive effects on both cardiovascu- over half indicated ‘unusual physical exertion’ as a trigger.
lar health and the muscle, and thus may be therapeutic in Bruckert et al. (2005) also report the prevalence of myalgia
itself to many individuals prescribed statins. With aberrant to be greater in physically active individuals. Though com-
skeletal muscle regeneration reported as a result of statins, pelling, it is important to consider that all participants were
however, the necessity for repeated skeletal muscle repair statin users on high-dose statin therapy; the prevalence of
following regular exercise may pose a problem. Taken myalgia reported here is likely an overrepresentation of the
together, the above preclinical studies suggest that statins prevalence in the general public. Additionally, this study
delay muscle regeneration and impede satellite cell function. does not discriminate between aerobic and resistance activ-
It is recognized that the aforementioned studies use extreme ity and only unusual (not regular) physical activity is defined
models of damage that do not represent exercise-induced as a trigger. Thompson et al. (1997) demonstrated serum CK
damage in humans and the observed delays in repair may levels to be elevated in statin users compared to non-users
not affect functional measures. Clearly, more research that following treadmill exercise, indicating a greater presence of
evaluates the effects of statins on muscle repair, particularly muscle damage. These serum CK levels returned to baseline
exercise-induced damage in humans, must be conducted to within 3 days.
elucidate these effects in humans. Reports that demonstrate myopathy and rhabdomyolysis
following exercise are large contributors to the apprehension
around physical activity and statin use (Parker et al. 2012;
Statins, aerobic metabolism and aerobic Semple 2012; Toussirot et al. 2015). This type of exercise
exercise capacity: general population is not representative of physical activity that would be pre-
scribed to improve statin users’ cardiovascular health. Thus,
Poor cardiorespiratory fitness (CRF) has repeatedly been dem- using it as evidence that physical activity is dangerous in
onstrated as a risk factor for CVD and mortality (Kubota et al. statin users is likely inappropriate. Additionally, rhabdomy-
2017; Myers et al. 2015; O’Donnell and Elosua 2008). Regu- olysis with statin use occurs in approximately 0.00003% of
lar participation in aerobic physical activity is the best way the population (Davidson et al. 2006) and presents more
to improve and maintain strong CRF. As such, an increase in commonly as a result of comorbidities or combined therapy
aerobic physical activity often accompanies a reduction in with other pharmaceuticals (Marot et al. 2000; Ozdemir
CVD risk. The mechanisms behind this phenomenon are not et al. 2000; Wu et al. 2009; Yeter et al. 2007).
limited to improved CRF, however. Reduced systolic/diastolic Multiple studies completed within the past 4 years have
blood pressure, blood lipids, blood cholesterol, arterial stiff- demonstrated that statin treatment does not negatively affect
ness, resting heart rate, and an increase in stroke volume and aerobic capacity (determined by differences in VO2max) or
angiogenesis are additional cardiovascular benefits of regular alter aerobic metabolism (Allard et al. 2018; Matuszek and
physical activity (Kubota et al. 2017; Myers et al. 2015). As Grant 2018; Morville et al. 2019). Morville et al. (2019)
13
Table 1 Summary of recent findings from studies investigating exercise interventions in statin users
Study Study design Sample size Participant demograph- Statin type, dose, treat- Aerobic exercise per- Anaerobic exercise SAMS?
ics ment length formance performance
Morville et al. (2019) Cross-sectional 84 Males/females Simvastatin No difference between No difference between N/A
Age: 40–70 years 40 mg/day statin users/non-users statin users/non-users
Average BMI: 28.3 kg/ Statin use for minimum No difference between No difference between
m2 3 months symptomatic/asymp- symptomatic/asymp-
Statin users with/ tomatic statin users tomatic statin users
without SAMS and
non-users
Allard et al. (2018) Cross-sectional 30 Males/females Atorvastatin, fluvas- No difference between No difference between N/A
Age: 54–68 years tatin, pravastatin, statin-treated/ placebo groups

Average BMI: 26.4 kg/ simvastatin groups
m2 10, 20, or 40 mg/day
Statin users and non- Statin use for minimum
users 3 months
Matuszek and Grant Within-patient control 16 Males/females Atorvastatin, rosuvasta- No difference when on/ N/A N/A
(2018) Age: 39–82 years tin, simvastatin off statin
Average BMI: 28.0 kg/ 10, 20, 40, or 80 mg/
m2 day
Statin users; treatment Statin use average
ceased and reintro- 3.6 years
duced
Baptista, Veríssimo, Randomized control 827 Males/females Atorvastatin, pitavasta- Improved CRF in exer- Improved in exercise No difference between
and Martins (2018) Age: > 60 years tin, pravastatin, rosu- cise group (independ- group (independent groups
Average BMI: 28.8 kg/ vastatin, simvastatin ent of statin use) of statin use)
m2 2, 10, or 20 mg/day
Statin users Statin use for minimum
1 year
Bahls et al. (2017) Cross-sectional 3500 Males/females Not reported Statin use inversely N/A N/A
Age: 20–79 years related to V
O2max in
Average BMI: 28.0 kg/ males but not females
m2
Statin users and non-
users
Mallinson et al. (2015) Cross-sectional 18 Males Atorvastatin, simvas- N/A No difference between Myalgia exacerbated in
Age: 69–72 years tatin groups 6/9 participants
Average BMI: N/A 20, 40, or 80 mg/day
Statin users with myal- Statin treatment for
gia and non-users minimum 1 year
Molina-Sotomayoret al. Randomized control 57 Females Lovastatin Improved CRF with N/A N/A
(2018) Age: > 60 years 20 mg/day exercise
Average BMI: N/A Treatment length not
Statin users reported
13

Table 1 (continued)
Study Study design Sample size Participant demograph- Statin type, dose, treat- Aerobic exercise per- Anaerobic exercise SAMS?
ics ment length formance performance
13
Zanetti et al. (2019) Randomised placebo 83 Males/females Rosuvastatin Improved CRF with Improved muscle N/A
control Age: 18–60 years 10 mg/day exercise (independent strength with exercise
Average BMI: 24.5 kg/ 12 weeks of treatment of statin use) (independent of statin
m2 use)
Statin-naïve, hyper-lipi-
demic and cholester-
olemic participants
with HIV diagnosis
for minimum 1 year
Kelly et al. (2016) Randomised control 2331 Males/females Atorvastatin, pravas- Improved CRF with N/A N/A
Age: 45–70 years tatin, simvastatin, exercise (independent
Average BMI: 30.0 kg/ ‘Other lipid lowering’ of statin use)
m2 Statin dose/treatment
Statin users and non- length not reported
users, ejection frac-
tion ≤ 35%
Toyama et al. (2017) Uncontrolled interven- 43 Males/females Not reported Trending towards N/A N/A
tion Age: 63–79 years increased CRF
Average BMI: 24.3 kg/
m2
Statin users with coro-
nary artery disease
Schwellnus et al. Cross-sectional 15,778 Males/females Not reported N/A N/A Statin use and running
(2018) Age: 18 + years experience posi-
Average BMI: N/A tively correlated with
Marathon race entrants exercise-associated
muscle cramping
Loenneke and Loprinzi Cross-sectional 2775 Males/females Atorvastatin, ceriv- N/A No difference between N/A
(2018) Age: 50–85 years astatin, fluvastatin, statin users/non-users
Average BMI: 28.0 kg/ lovastatin, pravasta-
m2 tin, simvastatin
Statin users and non- Treatment dose not
users reported
Statin use average
3 years
and Allard et al. (2018) recruited symptomatic and asymp-

tomatic statin users as well as untreated participants. These
researchers both demonstrated no differences in aerobic
capacity or metabolism between groups. It is unclear if
symptomatic statin user symptoms were exacerbated dur-
ing exercise, though the lack of an aerobic capacity differ-
SAMS?
ence demonstrates that subjects with SAMS did not prema-

No difference between N/A
turely stop activity. Allard et al. (2018) did demonstrate a

statin users/non-users
decrease in ventilatory threshold as well as increased lactate

concentration post-exercise with statin use. This indicates
Anaerobic exercise
that statin users, in particular symptomatic users, may rely

performance
more heavily on anaerobic metabolism during exercise. It is

important to note that the statin-naïve subjects evaluated in
both of these studies were dyslipidemic and, therefore, may
represent a less healthy portion of the population. In compli-
ance with ethical standards, used a within-subjects design,
Aerobic exercise per-
and participants were instructed to cease statin medication

for at least 3 weeks prior to performing submaximal tread-
mill exercise. After recommencing their statins for at least
formance
3 weeks, the same participants repeated the submaximal

Atorvastatin, lovastatin, N/A
exercise test. The investigators demonstrated no differences

in physiological characteristics between visits, including fat
Statin use 0.3–10 years
Sample size Participant demograph- Statin type, dose, treat-
oxidation, carbohydrate oxidation, and lactate concentra-

pravastatin, simvas-
tion. Interestingly, Bahls et al. (2017) demonstrated a nega-

Statin users: 29.9 kg/m2 10, 20, 40 mg/day
tive effect of statins on aerobic capacity in males, but not

ment length
females, indicating that statins may have sex-specific effects.

Given that, for the majority, statin treatment does not
tatin
negatively affect aerobic capacity or metabolism, the abil-

ity of statins to improve aerobic capacity with physical
significantly different
activity was investigated. Baptista et al. (2018) recruited

Statin users and non-
25.4 kg/m2 (*BMI
and assigned participants to 1 of 3 groups: statin interven-

between groups)
Age: 68–72 years
Statin non-users:
tion, statin plus exercise intervention, or exercise interven-

Males/females
Average BMI:
tion alone. The exercise intervention consisted of combined

aerobic (progressive upper and lower extremity movements),
users
anaerobic, and balance training. Participants in both the

ics
exercise and statin plus exercise intervention groups had

improved CRF and functional status, whereas statin treat-
ment alone caused a moderate reduction in these measures.
Importantly, participants did not note any abnormal symp-
24
toms of muscle pain. While these findings demonstrate that

physical activity is safe for statin users and that statins do
not reduce the positive effects of aerobic physical activity,
Cross-sectional
these interventions were conducted in a healthy population

Study design
that would not otherwise be prescribed statins. High choles-

terol levels and/or an elevated risk of metabolic disease may
predispose for greater statin-induced impairments to aerobic
fitness, and these populations should also be investigated.
Though aerobic physical activity has been demonstrated
Table 1 (continued)
Rengo et al. (2016)
as safe for the majority of statin users, many of the afore-

mentioned studies excluded statin users with multiple
comorbidities, and thus the effect of physical activity in
these populations cannot be discussed. In combination, how-
Study
ever, these studies provide evidence that statins do not alter
13
aerobic capacity or mitigate the positive effects of physical accumulation and cytochrome-oxidase negative fibers, sug-
activity. In this light, healthcare professionals should rec- gesting an intrinsic muscle deficit rather than weakness due
ommend regular moderate aerobic physical activity, as it is to neuropathy or decreased physical activity. Interestingly,
more likely to have positive, rather than negative, effects. both muscle strength and biopsy abnormalities resolved
Similarly, statin users should not avoid aerobic physical within 3 to 5 months of cessation of statin therapy. An intrin-
activity in fear of inducing or exacerbating their symptoms sic muscle defect was also identified in a small study of both
as current evidence demonstrates that regular, moderate asymptomatic and symptomatic statin users during electri-
physical activity is unlikely to cause these issues (Allard cal quadriceps stimulation, further suggesting a deficiency
et al. 2018; Baptista et al. 2018; Molina-sotomayor et al. independent of a neural impairment or of the participant’s
2018; Matuszek and Grant 2018; Morville et al. 2019). If a effort or motivation (Allard et al. 2018).
patient does withhold from participating in aerobic physical Larger scale studies, however, have not provided evidence
activity in fear of exacerbating SAMS, or if SAMS present to support an intrinsic loss of muscle strength with statin
or become aggravated with aerobic physical activity, it may prescription (Loenneke and Loprinzi 2018; Scott et al. 2009;
be worth considering replacing statin pharmacotherapy with Parker et al. 2013). In particular, there are limited data to
prescribed aerobic physical activity, which reduces blood suggest that statins directly impair resistance exercise capac-
lipids and cholesterol as well (Mann et al. 2014). Addition- ity independent of changes to physical activity levels. Even
ally, physical activity provides many systemic health ben- when no change to physical activity levels occurred, as in the
efits that statins cannot, including improved muscle health, interventional STOMP study, statin treatment did not induce
cognitive function, functional capacity, and quality of life a decrease in either upper or lower limb muscle strength
(Baptista et al. 2018; Kubota et al. 2017; McPhee et al. 2016; (Parker et al. 2013). Notably, limited studies have specifi-
Molina-sotomayor et al. 2018; Myers et al. 2015). Overall, cally considered muscle strength differences between symp-
aerobic physical activity should not be avoided until SAMS tomatic and asymptomatic statin users. Initial case reports
are induced or exacerbated, as the benefits of combination identifying muscle strength deficits with statin use found that
physical activity and statin treatment outweigh the risks of only symptomatic statin users had losses to muscle strength
being an inactive statin user. independent to changes in physical activity levels (Phillips
et al. 2002). However, a small study by Panza et al. (2016)
failed to confirm these original findings. A more thorough
Statins and anaerobic exercise function analysis of muscle strength in combination with simultane-
and capacity: general population ous muscle biopsies would clarify to what extent sympto-
matic statin users experience intrinsic muscle defects and
Regular participation in anaerobic or resistance exercise has the impact on muscle strength.
been demonstrated to reduce functional declines in muscle In a state-of-the-art placebo-controlled study, Parker et al.
strength associated with aging, improve insulin resistance (2013) introduced statin-naïve participants to atorvastatin or
and glucose metabolism, reduce body fat, and improve mark- placebo treatment and assessed muscle symptom presenta-
ers of cardiovascular health (American College of Sports tion and strength. The same proportion of statin and placebo-
Medicine Position Stand 1998; Fagard 2006; Hurley and treated participants developed myalgia; however, symptom
Hagberg 1998; Kraschnewski et al. 2016; Mavros et al. presentation differed between treatment groups. Symptom
2017; Patel et al. 2017; Roth et al. 1999; Westcott 2012; onset was earlier in statin-users and was more localized to
Winett and Carpinelli 2001). The CSEP Canadian Physical the extremities, whereas symptom presentation was general
Activity Guidelines recommend 2 days of muscle strength- whole-body or localized to an area of previous injury in
ening exercise per week regardless of age (Canadian Society placebo-treated participants. Statin users with SAMS also
for Exercise Physiology 2017). Given that statins have been had lower muscle strength in 4 of 15 strength tests. While
demonstrated to alter muscle metabolism at the ultrastruc- muscle ultrastructure was not assessed in this study, it pro-
tural level, below we discuss the evidence of whether these vides strong evidence for the nocebo effect and suggests that
changes translate clinically in terms of muscle strength and statins alter muscle physiology enough to affect strength.
function, and whether resistance exercise is effective and Of note, statin treatment did not reduce volitional physical
safe for statin users. activity more than placebo treatment; however, differences
Evidence for a reduction in muscle strength with statin between symptomatic and asymptomatic statin users were
prescription was first noted in a series of case reports from not reported.
4 patients in which symptomatic statin users experienced In compliance with ethical standards, found no differ-
weakness upon strength testing that reversed when statin ences in lean body mass, knee extensor or handgrip strength
treatment was discontinued (Phillips et al. 2002). Muscle between statin users and non-users independent of symptom
biopsies from this population indicated abnormal lipid presentation. Muscle biopsy analysis, however, demonstrated
13
that non-users had significantly more type IIX fibers than comorbid cardiovascular disease and advanced age > 65
statin users. This difference supports previous reports that (Nguyen et al. 2018).
statins differentially affect muscle fiber type, however, in the CVD comorbidity is a risk factor for both myopathy and
absence of impeding functional measures. Additional studies rhabdomyolysis (Nguyen et al. 2018) and has been an exclu-
support the findings of no differences in maximal isometric sion criterion in many of the previously examined studies.
knee extensor strength between statin users and statin-naïve Given that this population is one who are largely prescribed
subjects (Allard et al. 2018; Mallinson et al. 2015). As the statins, special attention should be given to their exercise
aforementioned studies demonstrate minimal differences in health. In compliance with ethical standards, investigated the
strength between subjects, it is inferred that muscle pain, effects of combination statin and aerobic exercise (station-
if present, did not affect muscle strength or exercise capa- ary cycling or treadmill running) training in patients with
bilities. In combination, these studies suggest that statins’ chronic heart failure and found exercise training to increase
alterations to skeletal muscle metabolism are insufficient to peak oxygen capacity and 6-min walking distance. Impor-
cause strength impairments. tantly, statin users and non-users saw similar gains with
Next, it is valuable to determine whether strength gains exercise. Similarly, König et al. (2005) recruited patients
and positive adaptations to resistance training are affected with diagnosed stable coronary heart disease that partici-
by statin treatment. Notably, two studies have found that pated in regular outpatient exercise groups. These research-
resistance training in combination with statin treatment had ers demonstrated that in combination, lipid-lowering drugs
positive effects (Baptista et al. 2018; Zanetti et al. 2019). and physical activity were more effective at reducing inflam-
Baptista et al. (2018) demonstrate that statin users assigned matory parameters related to morbidity and mortality than
to an exercise intervention group improved upper and lower pharmaceuticals alone. Furthermore, Toyama et al. (2017)
body limb strength to the same degree as exercising partici- demonstrated that combination statin therapy and aerobic
pants not taking statins. In contrast, statin users that were exercise training in patients with coronary artery disease
not part of the exercise intervention saw declines in func- did not cause any adverse events, indicating that aerobic
tional measures supporting the premise that statin users are exercise is safe for statin users with coronary artery disease.
at greater health risk when inactive. Particularly interesting is a recent study which demonstrated
Though well established that statins alter muscle metabo- that exercise promotes cardiomyogenesis and extends the
lism, the findings from the current analysis do not support regenerative capacity of the mouse heart following myocar-
that these alterations translate to systemically impair muscle dial infarction (Vujic et al. 2018). As cardiomyocyte death
strength. Additionally, there is little evidence that resistance contributes largely to heart failure, this increase in myogen-
exercise seriously exacerbates SAMS. These findings should esis seen with exercise may have positive implications for
encourage statin users to engage in resistance activity to this population of human subjects.
improve and/or avoid reductions in functional health. If sta- Physical activity is integral for delaying age-related func-
tin users are nervous to commence resistance training due to tional declines (McPhee et al. 2016), and statins have been
the possibility of inducing or exacerbating symptoms, they demonstrated to increase older adults’ risk for sarcopenia
should be encouraged to avoid unusual exertion and work at (Herghelegiu et al. 2018). While a potential exacerbation
low intensities, as even small increases in activity can have of the adverse effects of statins has been shown to occur in
large positive effects on muscle strength (Deplanque et al. the elderly (Golomb 2005; Herghelegiu et al. 2018), this
2012; Heesch et al. 2012; Hupin et al. 2015; Warburton et al. does not appear to be the case for resistance exercise capac-
2006). ity (Agostini et al. 2007; Mallinson et al. 2015; Panayiotou
et al. 2013; Rengo et al. 2016). While Mallinson et al. (2015)
found that symptomatic statin users did take longer to reach
Statins, aerobic exercise, and anaerobic peak power, resulting in less work output; this was concluded
exercise: high‑risk populations to be due to joint- and muscle-related discomfort and not
an intrinsic muscle deficit. It is important to highlight that
As previously established, current evidence supports that studying statin-induced muscle deterioration in the elderly is
statins alter skeletal muscle metabolism, but that for the confounded by the high incidence of muscle dysfunction and
majority of the population, these alterations are insufficient sarcopenia in this population. Pre-existing losses to muscle
to cause clinical changes in aerobic or anaerobic function mass, quality, and strength may be too pronounced for addi-
and performance. The populations analyzed in this review tional statin-induced deficits to be identified. Therefore, it
thus far have represented the general population of statin is possible that statins do have a detrimental effect on this
users. This section aims to more closely examine the impact population but those changes may be masked by variability
of statins on physical activity and exercise capacity in higher amongst subjects in their age-induced deficits.
risk SAMS populations. Common SAMS risk factors include
13
To determine whether statin treatment and concomitant health care professionals from prescribing physical activity
physical activity are safe in the elderly population, Hender- to their statin-prescribed patients.
son et al. (2016) recruited men and women aged 70 to 89 and The current review demonstrates that statins do alter
at high-risk of mobility disability. Of those recruited, statin skeletal muscle metabolism, in particular, mitochondrial
users and non-users were randomly assigned to exercise metabolism. The mechanism(s) behind SAMS, however, still
intervention (aerobic, resistance, and balance exercises) or lack consensus. Our summation of the evidence leads us to
control groups. Aerobic physical activity consisted of 30 min suggest that the etiology of SAMS development is likely
of walking at a moderate intensity. Following intervention, multifactorial. Placebo-control trials that manipulate and
it was demonstrated that the exercise group had significantly control for these multiple variables are, therefore, needed
reduced onset of mobility disability. Reduced systolic blood to further elucidate the mechanism(s) behind SAMS. The
pressure and reduced risk of diabetes, heart attack, stroke, demonstrated alterations to the skeletal muscle at the cellular
and peripheral artery disease were also demonstrated with level do not, however, appear to cause functional deficits for
exercise. Importantly, statin use did not attenuate the posi- the majority of the population; demonstrated by the lack of
tive impact of exercise and no adverse events were docu- differences between statin users and non-users in both anaer-
mented. Similarly, in compliance with ethical standards, obic and aerobic physical activity test parameters (Agostini
Molina-Sotomayor et al. demonstrated that progressive et al. 2007; Allard et al. 2018; Bahls et al. 2017; Baptista
walking training is safe and effective in older women on et al.2018; El-Salem et al. 2011; Henderson et al. 2016; Hen-
statin therapy. Moreover, combination of statin and exercise nessy et al. 2016; Loenneke and Loprinzi 2018; Mallinson
therapy proved effective in improving functional status, cho- et al. 2015; Matuszek and Grant 2018; Molina-sotomayor
lesterol management, and overall cardiovascular health in a et al. 2018; Morville et al. 2019; Parker et al. 2013; Rengo
cohort of dyslipidemic older adults whereas statin prescrip- et al. 2016; Scott et al. 2009; Zanetti et al. 2019). Given the
tion alone negatively affected cardiorespiratory health (Bap- cardiovascular, cognitive, and overall benefits of a physically
tista et al. 2018). In conjunction, these studies demonstrate active lifestyle, statin users should be encouraged to engage
that physical activity is not only safe but also beneficial for in regular, moderate level anaerobic and aerobic physical
the elderly population taking statins. activity. Physical activity does indeed provide very similar
The current evidence does seem to support that extreme cardiovascular benefits to statins in terms of blood lipid and
high-intensity exercise may increase the risk of SAMS vascular resistance in the absence of negative muscle side
(Parker et al. 2012; Schwellnus et al. 2018; Toussirot effects (Fig. 2); therefore, it should be prescribed to hyper-
et al.2015). Importantly, this type of exercise is not repre- cholesterolemic and dyslipidemic individuals as a first line
sentative of the type and intensity of physical activity that of treatment (Fulcher et al. 2018; Kubota et al. 2017; Lefferts
would be prescribed for cardiovascular health benefits in et al. 2018; McPhee et al. 2016; Myers et al. 2015). Alternate
elderly or cardiovascular subjects; those both at greater risk to statin medication, moderate physical activity improves
of SAMS and necessitating statin prescription. muscle health at both a structural and functional level. If
statin medication does need to be prescribed, patients should
be encouraged to also engage in regular physical activity.
Discussion and conclusion Health care professionals should aim to reduce fear sur-
rounding physical activity in statin users to encourage a
This review aimed to identify and summarize the current healthy lifestyle and reduce nocebo effects.
mechanistic evidence for SAMS and determine if these A limitation of many studies included in this review is
mechanisms may lead to alterations in exercise capacity that the sample population of statin users recruited had
and performance. Finally, we aimed to elucidate, based on been receiving statin therapy for extended periods of time.
current evidence, the efficacy and safety of combination sta- This may have led to an underrepresentation of SAMS
tin and physical activity prescription. Established literature given that SAMS typically present 4 to 6 weeks after the
has demonstrated that statins reduce muscle strength during initiation of statin treatment (Parker et al. 2013). Addi-
strength testing, as well as elevate serum CK both at rest tionally, statin users with more severe SAMS may have
and after exercise (Bouitbir et al. 2016; Parker et al. 2013; already stopped medication and/or are less prone to par-
Parker et al. 2012; Toussirot et al.2015), raising the concern ticipate in a study that has the potential to worsen their
that physical exertion may exacerbate muscle damage. The symptoms. This would also reduce the treatment effects
fear surrounding SAMS and physical activity may actually demonstrated in these studies. Importantly, however, the
play a role in nocebo effect that has been demonstrated in findings of this review indicate that long-term statin users
placebo-control studies (Parker et al. 2013), thus we aimed should not avoid physical activity in fear of inducing or
to determine if this fear was evidence based and should limit exacerbating symptoms.
13
Fig. 2 Schematic of the benefits (green) and disadvantages (red) (2019), Rebalka et al. (2019). 4, Allard et al. (2018), Bouitbir et al.
of statin treatment and regular physical activity, as discussed in this (2016), Morville et al. (2019), Parker et al. (2013). 5, Artinian et al.
review. References supporting each mechanism correspond to the (2010), Hupin et al. (2015), Kubota et al. (2017), Oja et al. (2017),
superscript numbers within the figure and are detailed below. 1, Paffenbarger et al. (2001), Sharman et al. (2015), Thompson et al.
Banach et al. (2015), Berthold et al. (2006), Bogsrud et al. (2013), (2003). 6, Istvan and Deisenhofer (2010), Law et al. (2003), Zhou
Bookstaver et al. (2012), Marcoff and Thompson (2007), Mor- and Liao (2010). 7, Fagard (2006). 8, Lefferts et al. (2018), Zhou and
rison et al. (2016), Qu et al. (2018), Rott et al. (2016), Taylor et al. Liao 2010. 9, Deplanque et al. (2012), Heesch et al. (2012), Hupin
(2015), Young et al. (2007). 2, Bruckert et al. (2005), El-Salem et al. et al. (2015), Mavros et al. (2017), Warburton et al. (2006), Winett
(2011), Fernandez et al. (2011), Gupta et al. (2017), Pasternak et al. and Carpinelli (2001). 10, Myers et al. (2015), O’Donnell and Elo-
(2002), Sathasivam and Lecky (2008), Thompson et al. (2016). 3, sua (2008), Patel et al. (2017). 11, Oja et al. (2017). 12, Mavros et al.
Allard et al. (2018), Bouitbir et al. (2016), Busanello et al. (2017), (2017), Molina-sotomayor et al. (2018), Toyama et al. (2017)
Dohlmann et al. (2019), Mallinson et al. (2015), Panajatovic et al.
In conclusion, our review demonstrates that statins do Compliance with ethical standards
not impair exercise adaptations or reduce exercise capacity
for the majority of the population. Engaging in anaerobic Conflict of interest The authors declare that they have no conflict of
and aerobic physical activity is safe and effective for statin interest.
users and should be prescribed as a first line of treatment for Ethical approval Approval from the institutional review board was not
hypercholesterolemic and dyslipidemic individuals as well required for completion of this manuscript.
as those who are unable to tolerate statin therapy. The evi-
Informed consent For this retrospective review, formal consent is not
dence that is currently available indicates that the benefits
required.
of engaging in physical activity while on statin medication
largely outweigh the risks.
Funding This study was funded by the Natural Sciences and Engi- References
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European Journal of Applied Physiology

The impact of statins on physical activity and exercise capacity:

Received: 22 December 2019 / Accepted: 24 March 2020

Abbreviations CVD Cardiovascular disease

Introduction soreness, weakness, cramps, and aches in the upper and/

Vitamin D Interestingly, when SERCA activity was assessed in statin

Age: 54–68 years tatin, pravastatin, statin-treated/ placebo groups

and Allard et al. (2018) recruited symptomatic and asymp-

ence demonstrates that subjects with SAMS did not prema-

turely stop activity. Allard et al. (2018) did demonstrate a

decrease in ventilatory threshold as well as increased lactate

that statin users, in particular symptomatic users, may rely

more heavily on anaerobic metabolism during exercise. It is

and participants were instructed to cease statin medication

3 weeks, the same participants repeated the submaximal

exercise test. The investigators demonstrated no differences

oxidation, carbohydrate oxidation, and lactate concentra-

tion. Interestingly, Bahls et al. (2017) demonstrated a nega-

tive effect of statins on aerobic capacity in males, but not

females, indicating that statins may have sex-specific effects.

negatively affect aerobic capacity or metabolism, the abil-

activity was investigated. Baptista et al. (2018) recruited

and assigned participants to 1 of 3 groups: statin interven-

tion, statin plus exercise intervention, or exercise interven-

tion alone. The exercise intervention consisted of combined

anaerobic, and balance training. Participants in both the

exercise and statin plus exercise intervention groups had

toms of muscle pain. While these findings demonstrate that

these interventions were conducted in a healthy population

that would not otherwise be prescribed statins. High choles-

Rengo et al. (2016)

as safe for the majority of statin users, many of the afore-

ever, these studies provide evidence that statins do not alter

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Abbreviations CVD Cardiovascular disease