A short-term statin treatment changes the contractile properties of fast-twitch skeletal muscles (original) (raw)
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Effect of Statins on Skeletal Muscle Function
Circulation, 2013
H ydroxy-methyl-glutaryl CoA reductase inhibitors or statins are the most effective medications for reducing elevated concentrations of low-density lipoprotein (LDL) cholesterol and produce remarkable reductions in cardiovascular events. 1 Statins can produce life-threatening rhabdomyolysis, but this is rare. 2 Statins are more frequently associated with mild muscle complaints, including myalgia, cramps, and weakness, which may compromise medication compliance and quality of life. The reported incidence of myalgia during statin therapy ranges from 1% in controlled studies 3 to 25% in clinical reports. 4 Muscle weakness has also been reported with statin therapy, but muscle performance and exercise performance have not been carefully studied. 5 Clinical Perspective on p 103 The Effect of Statins on Muscle Performance study (STOMP; National Heart, Lung, and Blood Institute 5R01HL081893, NCT00609063) determined the incidence of statin-associated muscle complaints and examined the effect of statins on muscle performance and exercise capacity by administering atorvastatin 80 mg daily or placebo to healthy subjects for 6 months or until subjects developed myalgia. Methods Study Overview STOMP was a double-blind, random-assignment clinical trial; the methods used have been described previously. 6 Equal numbers of men and women across 3 age ranges (20-39, 40-54, and ≥55 years) were recruited over 4 years. Baseline lipid, liver, kidney, thyroid, and creatine kinase (CK) measurements were obtained. Subjects completed a baseline muscle symptom questionnaire and exercise testing, including a maximal exercise test with gas analysis; hand grip, elbow flexor, and knee extensor strength testing; and a knee extensor endurance exercise test. Subjects were then randomly assigned in a double-blind fashion to identical placebo or atorvastatin 80 mg daily (Lipitor; Pfizer, Inc, New York, NY). Atorvastatin tablets were crushed for compounding, but this does not influence relative bioavailability of the statin (Medical Information Letter 337882; Pfizer, Inc) Subjects were called twice monthly to ascertain symptoms. Subjects performed repeat testing after 6 months or after they developed muscle symptoms meeting the study definition of statin-induced myalgia. The study was approved by the Institutional Review boards at Hartford Hospital, the University of Massachusetts, Background-Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. Methods and Results-The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). Conclusions-These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance.
characteristics of statin‐induced muscle injury as well as clinical features of patients who develop this condition in terms of frequency and pattern of evolution. Materials and Methods: Forty patients (age 39‐74 years) including 25 subjects with type 2 diabetes mellitus, 9 with cardiovascular diseases and 6 with hyperlipidemia, who were receiving atrovastatin 40 mg/day for variable period, were studied. Thirty three healthy subjects (age 31‐74 years) served as control group. Creatine phosphokinease level, thyroid function, motor unit potential parameters and muscle fiber conduction velocity of biceps brachii and tibialis anterior muscles were measured. Results: Creatine phosphokinase level was elevated in statin users, particularly in those with diabetes mellitus. Less than 50% of statin users experienced symptoms related to muscle injury. Muscle fiber conduction velocity of the biceps brachii muscle was significantly reduced. Statin users with diabetes mellitus showed significant changes in electrophysiological parameters as compared to those with cardiovascular diseases and hyperlipidemia. Muscle biopsies showed muscle fiber variation in size, fibrosis and mild inflammatory cell infiltration. Immunohistochemical evaluation of muscle biopsies showed positive expression of Bcl‐2 and one patient showed positive P53 immunohistochemical expression with elevated level of creatine phosphokinase. Conclusion: Atorvastatin increased average creatine kinase, statins produce mild muscle injury even in asymptomatic subjects. Diabetic statin users were more prone to develop muscle injury than others. Muscle fiber conduction velocity evaluation is recommended as a simple and reliable test to diagnose statin‐induced myopathy instead of invasive muscle biopsy.
Effects of statins on skeletal muscle: a perspective for physical therapists
Physical therapy, 2010
Hyperlipidemia, also known as high blood cholesterol, is a cardiovascular health risk that affects more than one third of adults in the United States. Statins are commonly prescribed and successful lipid-lowering medications that reduce the risks associated with cardiovascular disease. The side effects most commonly associated with statin use involve muscle cramping, soreness, fatigue, weakness, and, in rare cases, rapid muscle breakdown that can lead to death. Often, these side effects can become apparent during or after strenuous bouts of exercise. Although the mechanisms by which statins affect muscle performance are not entirely understood, recent research has identified some common causative factors. As musculoskeletal and exercise specialists, physical therapists have a unique opportunity to identify adverse effects related to statin use. The purposes of this perspective article are: (1) to review the metabolism and mechanisms of actions of statins, (2) to discuss the effects of statins on skeletal muscle function, (3) to detail the clinical presentation of statin-induced myopathies, (4) to outline the testing used to diagnose statin-induced myopathies, and (5) to introduce a role for the physical therapist for the screening and detection of suspected statin-induced skeletal muscle myopathy.
Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle
Biochemical Pharmacology, 2011
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Electrophysiologic and clinico-pathologic characteristics of statin-induced muscle injury
Iranian Journal of Basic Medical Sciences, 2015
In this study, we aimed at evaluation of electrophysiological and histopathalogical characteristics of statin-induced muscle injury as well as clinical features of patients who develop this condition in terms of frequency and pattern of evolution. Forty patients (age 39-74 years) including 25 subjects with type 2 diabetes mellitus, 9 with cardiovascular diseases and 6 with hyperlipidemia, who were receiving atrovastatin 40 mg/day for variable period, were studied. Thirty three healthy subjects (age 31-74 years) served as control group. Creatine phosphokinease level, thyroid function, motor unit potential parameters and muscle fiber conduction velocity of biceps brachii and tibialis anterior muscles were measured. Creatine phosphokinase level was elevated in statin users, particularly in those with diabetes mellitus. Less than 50% of statin users experienced symptoms related to muscle injury. Muscle fiber conduction velocity of the biceps brachii muscle was significantly reduced. Sta...
Preventive Cardiology, 2010
Hydroxymethylglutaryl-coenzyme A reductase inhibitors or statins are the most effective medications for reducing elevated concentrations of lowdensity lipoprotein cholesterol (LDL-C). Statins reduce cardiac events in patients with coronary artery disease and previously healthy persons. Current recommendations for LDL-C treatment goals indicate that more patients will be treated with higher doses of these medications. Statins have been extremely well-tolerated in controlled clinical trials but are increasingly recognized to produce skeletal muscle myalgia, cramps, and weakness. The reported frequency of such mild symptoms is not clear, and muscle performance has not been examined with these medications. Accordingly, the present investigation, the Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study, will recruit approximately 440 healthy persons. Participants will be randomly assigned to treatment with atorvastatin 80 mg ⁄ d or placebo. Handgrip, elbow and knee isometric and isokinetic strength, knee extensor endurance, and maximal aerobic exercise performance will be determined at baseline. Participants will undergo repeat testing after 6 months of treatment or after meeting the study definition of statin myalgia. This study will determine the effect of statins on skeletal muscle strength, endurance, and aerobic exercise performance and may ultimately help clinicians better evaluate statin-related muscle and exercise complaints. Prev Cardiol.
Fluvastatin-induced alterations of skeletal muscle function in hypercholesterolaemic rats
Journal of Muscle Research and Cell Motility, 2011
Although statins, the most widely used drugs in the treatment of hyperlipidaemia, are generally accepted as efficient and safe drugs their side-effects on skeletal muscle have been reported with increasing frequency in the past years. The lack of an appropriate animal model in which these side effects would consistently be observed is one of the most important drawbacks in studying statin associated myopathy. To overcome this and enable the studying of the effects of fluvastatin on skeletal muscles an animal model with high blood cholesterol levels was developed. In these animals cholesterol levels rose more than seven fold (from 1.5±0.1 to 10.7±2.0 mmol/L; n=15 and 16) with a dramatic increase in LDL/HDL ratio (from 0.29±0.02 to 1.56±0.17). While the latter was reversed by statin treatment, an elevation in blood creatine kinase level indicated the presence of muscle wasting. Fibers from m. extensor digitorum longus (EDL) showed significant reduction in cross sectional area in the statin treated groups. Statin treatment also decreased the proliferation and fusion of skeletal myotubes in culture. In line with this, resting intracellular calcium concentration ([Ca 2+ ] i) was reduced in statin treated satellite cells and myotubes. On the other hand, in adult skeletal muscle fibers statin treatment increased resting [Ca 2+ ] i (116±4 vs. 151±5 nM; n= 33 and 34) and decreased both twitch and tetanic force both in EDL and m. soleus. In addition, in m. soleus the duration of twitch and tetanic force was shortened. These results clearly indicate that statin administration in these animals results in a myopathy characterized by decreased muscle force and elevated plasma creatine kinase level.
British Journal of Pharmacology, 2006
Background and purpose: Skeletal muscle injury by hypolipidemic drugs is not fully understood. An extensive analysis of the effect of chronic treatment with fluvastatin (5 mgkg -1 and 20 mgkg -1 ), atorvastatin (10 mgkg -1 ) and fenofibrate (60 mgkg -1 ) on rat skeletal muscle was undertaken. Experimental approach: Myoglobinemia as sign of muscle damage was measured by enzymatic assay. Histological and immunohistochemical techniques were used to estimate muscle integrity and the presence of aquaporin-4, a protein controlling water homeostasis. Electrophysiological evaluation of muscle Clconductance (gCl) and mechanical threshold (MT) for contraction, index of intracellular calcium homeostasis, was performed by the two-intracellular microelectrodes technique. Key results: Fluvastatin (20 mgkg -1 ) increased myoglobinemia. The lower dose of fluvastatin did not modify myoglobinemia, but reduced urinary electrolytes, suggesting direct effects on renal function. Atorvastatin also increased myoglobinemia, with slight effects on urinary parameters. No treatment caused any histological damage to muscle or modification in the number of fibres expressing aquaporin-4. Either fluvastatin (at both doses) or atorvastatin reduced sarcolemma gCl and changed MT. Both statins produced slight effects on total cholesterol, suggesting that the observed modifications occur independently of HMGCoA-reductase inhibition. Fenofibrate increased myoglobinemia and decreased muscle gCl, whereas it did not change the MT, suggesting a different mechanism of action from the statins. Conclusions and Implications This study identifies muscle gCl and MT as early targets of drugs action that may contribute to milder symptoms of myotoxicity, such as muscle cramps, while the increase of myoglobinemia is a later phenomenon.
Statins affect skeletal muscle performance: evidence for disturbances in energy metabolism
The Journal of clinical endocrinology and metabolism, 2017
Statin myopathy is linked to disturbances in mitochondrial function and exercise intolerance. To determine whether differences exist in exercise performance, muscle function and mitochondrial oxidative capacity and content between symptomatic and asymptomatic statin users, and non-statin using controls. Cross-sectional study. Department of Physiology of the Radboud University Medical Center. Long-term symptomatic (n=10) and asymptomatic (n=10) statin users, and controls (n=10). Maximal incremental cycling tests and involuntary electrically stimulated isometric quadriceps muscle contractions were performed and a muscle biopsy was obtained from the vastus lateralis muscle. Maximal exercise capacity, substrate utilization during exercise, muscle function, and mitochondrial energy metabolism. VO2peak, maximal work load and ventilatory efficiency were comparable between groups, but both statin groups had a depressed anaerobic threshold compared to controls (p=0.01). Assessment of muscle ...