You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
3-hydroxy-3-methylgutaryl coenzyme a ( hmg - coa ) reductase inhibitors ( statins ) are cholesterol - lowering drugs which work by blocking the rate - limiting step in the cholesterol synthesis pathway ( fig .
1 ) . stains are the most frequently and widely used medication in the treatment of cardiovascular disease , diabetes , and cancer to reduce cholesterol levels ( e.g. , ldl - cholesterol ) by inhibiting the formation of mevalonate ( a precursor to cholesterol ) , ubiquinone ( coenzyme q ) , and other compounds .
although statins have a number of beneficial effects including a lipid - lowering effect , improved endothelial function , anti - inflammation , and insulin sensitivity , statins , particularly lipophilic statins ( e.g. , simvastatin , atorvastatin , cerivastatin , and lovastatin ) , also cause adverse side effects in skeletal muscle ranging from mild to moderate muscle fatigue , weakness , and pain to fatal rhabdomyolysis [ 46 ] .
in fact , considering that the occurrence of less adverse side effects is not reported , the incidence of statin - induced myopathy may be 510% , and concerns about the safety of statins on skeletal muscle are expected to increase . however , the underlying mechanisms by which statins induce skeletal muscle side effects have not been clearly determined .
therefore , this review primarily focuses on statin - induced myopathy and the potential mechanisms of statin - associated myopathy .
in addition , this review provides an overview of the role of exercise in stain - induced myopathy .
statins , widely prescribed cholesterol - lowering drugs for the treatment of dyslipidemia and cardiovascular disease , are associated with skeletal muscle - related complaints or myopathies .
apoptosis is programmed cell death that is highly regulated and executed via the activation of caspase dependent or independent signaling . in general
, apoptosis plays an important role in governing development , growth , and repair in cells .
however , excessive apoptosis may be associated with dysfunction , disease , and myopathy in skeletal muscle .
it has been reported that statin treatment can induce apoptosis in skeletal muscle in both human [ 912 ] and rodent [ 1316 ] models .
for example , simvastatin treatment ( 5 m ) during 48 hours increased protein levels of proapoptotic protein bax and apoptosis marker tunel - positive nuclei in primary human skeletal muscle cells .
furthermore , kobayashi et al .   showed that cerivastatin treatment ( 100 m ) during 2472 hours elevated apoptosis in rhabdomyosarcoma cells from human subjects .
mitochondria play a central role in regulating homeostasis as well as inducing apoptosis in skeletal muscle .
therefore , mitochondrial dysfunction is associated with the increase in the susceptibility to apoptosis and oxidative stress in skeletal muscle .
previous studies showed that statins might impair mitochondrial function in the skeletal muscles of humans [ 1723 ] and animals , leading to myopathy .
for example , patients with hypercholesterolemia taking simvastatin ( 80 mg / day ) for 8 weeks displayed a decrease in mitochondrial respiratory chain enzyme and citrate synthase activities .
stains also inhibit the synthesis of ubiquinone ( coenzyme q10 ) , a major electron carrier in the mitochondrial respiratory chain
. however , statin treatment does not appear to consistently affect mitochondrial function in the whole body .
.   showed that fat oxidation and respiratory exchange ratio ( rer ) did not change in patients with hypercholesterolemia taking atorvastatin ( 40 mg / day ) for 8 weeks .
although numerous studies on statin - associated myopathy have been reported in animals and humans , the molecular mechanisms of statin - induced myopathy have not been completely elucidated .
a variety of hypotheses regarding potential mechanisms of statin - induced myopathy have been proposed to gain insight into myopathy in skeletal muscle , including ( a ) deficiency of ubiquinone , ( b ) reactive oxygen species ( ros ) production , and ( c ) induction of apoptosis .
ubiquinone is located in the mitochondrial respiratory chain , where it plays an essential role in transferring electrons from complex i and ii to complex iii associated with oxidative phosphorylation and energy production .
in addition , ubiquinone acts as a potent antioxidant in the inner mitochondrial membrane by scavenging free radicals .
however , it has been shown that statins reduced levels of ubiquinone in muscle and blood ( fig .
the rationale of statin - induced decrease in ubiquinone is the fact that statins can inhibit the biosynthesis of ubiquinone as well as cholesterol in the cholesterol synthesis pathway as shown in fig .
1 . for example , blood and muscle concentrations of ubiquinone were decreased after short- and long - term treatment with statins , which suggests that deficiency of ubiquinone in mitochondria may impair cellular respiration resulting in skeletal myopathy and that supplementation with ubiquinone may be an appropriate therapy to counteract adverse side effects of statin treatment .
in particular , superoxide ( o2 ) free radicals are generated from complex i ( mainly ) and complex iii in the electron transport system and changed to hydrogen peroxide ( h2o2 ) .
it has been recently reported that statin treatment increased oxidative stress in human skeletal muscle cells   and fibers   ( fig .
, we recently found that simvastatin treatment induced mitochondrial oxidative stress as indicated by increases in o2 and h2o2 production as well as impaired oxygen consumption supported by complex i substrates ( glutamate + malate ) .
in addition , it has been suggested that statin - induced myopathy is associated with apoptosis in skeletal muscle . as mentioned above , statins induce apoptosis in skeletal muscle , which may be an essential factor causing myopathy experienced by patients taking stains .
in general , apoptosis is induced through three major apoptotic signaling pathways : the ( a ) mitochondrial - driven pathway , ( b ) cytokines / fas - driven pathway , and ( c ) endoplasmic reticulum ( er)/ca - driven pathway .
however , statin - induced apoptosis in skeletal muscle may be mitochondrial - mediated as indicated by an increase in bax , release of cytochrome c , active caspase-9 , and caspase-3 by statin treatment . in particular ,
the increase in ros ( e.g. , o2 and h2o2 ) generation with statin treatment may play an important role in opening the mitochondrial permeability transition pore ( mptp ) , which results in caspase dependent ( e.g. , cytochrome c and caspase-9 ) or independent ( e.g. , apoptosis inducing factor [ aif ] and endog ) apoptosis in skeletal muscle ( fig .
3 ) , suggesting that statin - induced oxidative stress triggers mitochondrial - mediated apoptosis . for example , kwak et al .   demonstrated that simvastatin treatment induced apoptosis as well as oxidative stress in differentiated skeletal muscle cells .
exercise is regarded as one of the most cost effective ways to prevent metabolic and cardiovascular diseases and is recommended to patients as a lifestyle intervention to supplement drug therapy .
however , the benefit / risk of exercise with statin therapy has not been thoroughly investigated . to date , the effects of exercise frequency , intensity , time or type on the risk of statin - induced myopathy have not been well studied .
most studies of the interactions of exercise and statin therapy include an acute / single exercise and indirect measures of muscle damage ( i.e. , blood creatine kinase [ ck ] levels ) .
in contrast to statin - induced myopathy , chronic exercise training has the potential to counteract statin - induced side effects in skeletal muscle .
for example , endurance exercise training increases mitochondrial biogenesis and mitochondrial respiration , and decreases oxidative stress and apoptosis in skeletal muscle .
however , previous studies have shown inconsistent findings regarding the effects of exercise on statin - induced myopathy .
while some studies reported that exercise seemed to increase the risk of statin - induced myopathy [ 3337 ] , others suggested that exercise did not affect statin - induced myopathy [ 33,3842 ] .
for example , 12 weeks of aerobic exercise training in combination with simvastatin ( 40 mg / day ) decreased cardiorespiratory fitness and muscle citrate synthase activity in obese subjects .
in addition , 2 weeks of treadmill exercise increased muscle damage in rats taking cerivastatin ( 0.51.0 mg / kg / day ) for 2 weeks .
in contrast , 10 weeks of endurance and resistance exercise training did not affect serum ck in hypercholesterolemic patients taking rosuvastatin ( 10 mg / day ) for 20 weeks .
furthermore , meador and huey   showed that 4 weeks of wheel running exercise with cerivastatin treatment ( 1 mg / kg / day ) for 2 weeks prevented statin - associated force loss and increased fatigability in mice , suggesting that exercise prior to statin treatment can protect against statin - induced muscle dysfunction .
table 2 shows a summary of studies examining the effects of exercise on statin - induced myopathy in human and animal models .
although the mechanisms of statin - induced skeletal myopathy have not been determined , the mechanisms may be associated with ubiquinone deficiency , oxidative stress , and apoptosis . however
, the underlying molecular and cellular mechanism by which statins affect mitochondrial function and apoptosis in skeletal muscle remains unknown .
furthermore , it is not clear whether exercise exacerbates statin - associated myopathy in skeletal muscle . therefore , further studies of patients taking statins with different kinds of exercise are warranted to develop new strategies for statin - associated mitochondrial dysfunction and apoptosis leading to skeletal myopathy .
statins are widely used drugs to lower cholesterol levels and to reduce the risk of cardiovascular disease . 
 however , it has been reported that statins are associated with adverse side effects of skeletal myopathy . 
 statin treatment can impair mitochondrial function and induce apoptosis in skeletal muscle in both human and animal models . 
 ubiquinone plays an essential role in transferring electrons in the mitochondrial electron transfer chain for oxidative phosphorylation . 
 however , statin treatment reduces ubiquinone levels in the cholesterol synthesis pathway , which may be associated with mitochondrial dysfunction . 
 in addition , reactive oxygen species ( ros ) production and apoptosis induced by statins may provide cellular and molecular mechanisms in skeletal myopathy . 
 exercise is the most effective therapy to prevent metabolic and cardiovascular diseases . 
 however , whether exercise provides a benefit to or exacerbation of statin - induced myopathy in skeletal muscle remains poorly investigated . 
 this review will briefly provide a comprehensive summary regarding the effects of statins on skeletal myopathy , and discuss the potential mechanisms of statin - induced myopathy and the role of exercise in statin - induced myopathy in skeletal muscle .