Absence of anti–HMG‐CoA reductase autoantibodies in severe self‐limited statin‐related myopathy

Introduction: Patients with self‐limited statin‐related myopathy improve spontaneously when statins are stopped. In contrast, patients with statin‐associated autoimmune myopathy have autoantibodies recognizing 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR) and usually require immunosuppressive therapy to control their disease. On initial presentation, it can sometimes be difficult to distinguish between these 2 diseases, as both present with muscle pain, weakness, and elevated serum creatine kinase (CK) levels. The goal of this study was to determine whether patients with severe self‐limited statin‐related myopathy also make anti‐HMGCR autoantibodies. Methods: We screened 101 subjects with severe self‐limited cerivastatin‐related myopathy for anti‐HMGCR autoantibodies. Results: No patient with severe self‐limited cerivastatin‐related myopathy had anti‐HMGCR autoantibodies. Conclusion: Anti‐HMGCR autoantibody testing can be used to help differentiate whether a patient has self‐limited myopathy due to cerivastatin or autoimmune statin‐associated myopathy; these findings may apply to other statins as well. Muscle Nerve 54 : 142–144, 2016     

Immune‐mediated necrotizing myopathy associated with statins

We report patients from two neuromuscular centers who were evaluated between the years 2000 and 2008 and met the following criteria: (1) proximal muscle weakness occurring during or after treatment with statins; (2) elevated serum creatine kinase (CK); (3) persistence of weakness and elevated CK despite discontinuation of the statin; (4) improvement with immunosuppressive agents; and (5) muscle biopsy showing necrotizing myopathy without significant inflammation. Twenty‐five patients fulfilled our inclusion criteria. Twenty‐four patients required multiple immunosuppressive agents. Fifteen patients relapsed after being tapered off immunosuppressive therapy. Exposure to statins prior to onset was significantly higher in patients with necrotizing myopathy (82%) as compared to those with dermatomyositis (18%), polymyositis (24%), and inclusion‐body myositis (38%) seen in the same time period. The lack of improvement following discontinuation of statins, the need for immunosuppressive therapy, and frequent relapse when treatment was tapered suggest an immune‐mediated etiology for this rare, statin‐associated necrotizing myopathy. Muscle Nerve, 2010     

Low‐intensity running exercise enhances the capillary volume and pro‐angiogenic factors in the soleus muscle of type 2 diabetic rats

Introduction: We determined the effects of low‐intensity exercise on the three‐dimensional capillary structure and associated angiogenic factors in the soleus muscle of Goto‐Kakizaki (GK) diabetic rats. Methods: Four groups of male rats were studied: sedentary nondiabetic (Con), exercised nondiabetic control (Ex), sedentary GK, and exercised GK (GK+Ex). Rats in the Ex and GK+Ex groups were subjected to chronic low‐intensity running on a treadmill (15 m/min, 60 min/session, 5 sessions/week for 3 weeks). Results: Although mean capillary volume and diameter were lower in the GK compared with all other groups, low‐intensity exercise increased both of these measures in GK rats. Mitochondrial markers, i.e., SDH activity and PGC‐1α expression, and the levels of angiogenic factors were higher in the GK+Ex than all other groups. Exercise increased vascular endothelial growth factor (VEGF) protein levels and the VEGF‐to‐TSP‐1 ratio, an indicator of angiogenesis, in GK rats. Conclusions: Combined, the results indicate that low‐intensity exercise reduces some of the microcirculatory complications in type 2 diabetic muscles. Muscle Nerve 51: 391–399, 2015     

Oxidative capacity and fatigability in run-trained malignant hyperthermia-susceptible mice

Introduction: The purpose of this study was to test the hypothesis that malignant hyperthermia model mice (RyR1Y522S/wt) are more vulnerable to exercise‐induced muscle injury and fatigability and adapt less to run training. Methods: After 6 weeks of voluntary wheel running, we measured anterior crural muscle fatigability, muscle injury, and cytochrome oxidase (COX) and citrate synthase (CS). Results: Although RyR1Y522S/wt mice ran without undergoing MH episodes, they ran 42% less distance than wild‐type (WT) mice. Muscles from WT mice exhibited increased fatigue resistance and COX content after training. Muscles from RyR1Y522S/wt mice demonstrated no significant change in fatigability or COX and CS after training. However, muscles from RyR1Y522S/wt mice displayed less intrinsic fatigability and greater COX/CS content and muscle damage than WT mice. Conclusions: RyR1Y522S/wt mice can run without having rhabdomyolysis, and their inability to adapt to training appears to stem from intrinsic enhancement of mitochondrial enzymes and fatigue resistance. Muscle Nerve, 2012     

Evaluation of skeletal muscle during calf exercise by 31-phosphorus magnetic resonance spectroscopy in patients on statin medications

Muscle pain is a common side effect of statin medications, but the cause is poorly understood. We characterized phosphocreatine (PCr) exercise recovery kinetics in 10 patients with hypercholesterolemia before and after a 4-week regimen of statin therapy using 31-phosphorus magnetic resonance spectroscopy ((31) P-MRS). (31) P spectra were obtained before, during, and after exercise on a calf flexion pedal ergometer. Creatine kinase (CK) serum levels were drawn before and after statin therapy. The mean metabolic recovery time constant in subjects increased from 28.1 s (SE = 6.5 s) to 55.4 s (SE = 7.4 s) after statin therapy. The unweighted mean of the pre/post-recovery time difference was -27.3 s (SE = 12.4 s; P = 0.02). Pre- and post-therapy CK levels were not significantly different (P = 0.50). Metabolic recovery time in the calf is prolonged in patients after statin use. This suggests that statins impair mitochondrial oxidative function, and (31) P MRS is a potential study model for statin-associated myopathy.     

Statin-induced bilateral foot drop in a case of hypothyroidism

Muscle involvement is a common manifestation of both clinical and subclinical hypothyroidism, with serum creatine kinase (CK) elevation being probably the most common manifestation, and is seen in up to 90% of patients, but is usually mild (less than 10 times the upper limit of normal). Rhabdomyolysis is a distinctively uncommon presentation of hypothyroidism described usually in the setting of precipitating events such as strenuous exercise, alcohol, or statin use. Rarely rhabdomyolysis and myoedema seen in hypothyroidism can be complicated by the development of anterior compartment syndrome leading to neurovascular compression. We describe a case of a patient with hypothyroidism who developed acute onset bilateral foot drop on initiation of statins. This case highlights the need for cautious use of statins in patients at risk for rhabdomyolysis.     

Physical exercise during muscle regeneration improves recovery of the slow/oxidative phenotype

Introduction: As skeletal muscle mass recovery after extensive injury is improved by contractile activity, we explored whether concomitant exercise accelerates recovery of the contractile and metabolic phenotypes after muscle injury. Methods: After notexin‐induced degeneration of a soleus muscle, Wistar rats were assigned to active (running exercise) or sedentary groups. Myosin heavy chains (MHC), metabolic enzymes, and calcineurin were studied during muscle regeneration at different time points. Results: The mature MHC profile recovered earlier in active rats (21 days after injury) than in sedentary rats (42 days). Calcineurin was higher in the active degenerated than in the sedentary degenerated muscles at day 14. Citrate synthase and total lactate dehydrogenase (LDH) activity decreased after injury and were similarly recovered in both active and sedentary groups at 14 or 42 days, respectively. H‐LDH isozyme activity recovered earlier in the active rats. Conclusions: Exercise improved recovery of the slow/oxidative phenotype after soleus muscle injury. Muscle Nerve 55 : 91–100, 2017     

Physical exercise in myasthenia gravis is safe and improves neuromuscular parameters and physical performance‐based measures: A pilot study

Introduction: Due to the shortage of exercise‐related research in Myasthenia Gravis (MG), there are no consensus guidelines on physical exercise for MG patients. Methods: In this prospective pilot study, 10 MG patients with mild disease performed supervised aerobic and resistance training twice weekly for 12 weeks. The Myasthenia Gravis Composite (MGC) score, compound motor action potential (CMAP), repetitive nerve stimulation, muscle force, physical performance‐based measures, serum levels of interleukin‐6, muscle enzymes, and immuno‐microRNAs miR‐150‐5p and miR‐21‐5p were assessed before and after the training period. Results: Physical exercise was well tolerated, and the MGC score was unchanged. Muscle resistance weights and CMAP amplitudes increased for biceps brachii and rectus femoris muscles, and physical performance‐based measures improved. Muscle enzymes remained normal, whereas disease‐specific microRNAs miR‐150‐5p and miR‐21‐5p were reduced after the training period. Conclusions: We propose that general recommendations regarding physical exercise can be applied safely to well‐regulated MG patients. Muscle Nerve 56 : 207–214, 2017     

Exercise increases utrophin protein expression in the mdx mouse model of Duchenne muscular dystrophy

Introduction: Duchenne muscular dystrophy (DMD) is a lethal genetic disease caused by mutations in the dystrophin gene resulting in chronic muscle damage, muscle wasting, and premature death. Utrophin is a dystrophin protein homologue that increases dystrophic muscle function and reduces pathology. Currently, no treatments that increase utrophin protein expression exist. However, exercise increases utrophin mRNA expression in healthy humans. Therefore, the purpose was to determine whether exercise increases utrophin protein expression in dystrophic muscle. Methods: Utrophin protein was measured in the quadriceps and soleus muscles of mdx mice after 12 weeks of voluntary wheel running exercise or sedentary controls. Muscle pathology was measured in the quadriceps. Results: Exercise increased utrophin protein expression 334 ± 63% in the quadriceps relative to sedentary controls. Exercise increased central nuclei 4 ± 1% but not other measures of pathology. Conclusions: Exercise may be an intervention that increases utrophin expression in patients with DMD. Muscle Nerve 49 : 915–918, 2014     

Prevalence and risk factors of muscle complications secondary to statins

Introduction: The aim of the study was to investigate the prevalence and risk factors of muscle complications among patients using statins. Methods: We conducted a prospective comparative study on 345 patients receiving statins and compared the findings with an age‐ and gender‐matched control group of 85 subjects. Univariate and multivariate analyses with logistic regression models were used to study the association of different patient and disease characteristics with muscle complications. Results: Adverse reactions were reported by 21% of patients and 5.9% of controls (P = 0.0013). Objective weakness was found in 15% of the patients who reported muscle symptoms (3.2% of the total cohort), but not in controls. Older age, longer duration of statin use, diabetes, stroke, and lower body mass index were associated with increased risk of developing these symptoms. Conclusions: Adverse reactions to statins may be more common than previously reported, and they may be affected by specific patient and disease characteristics. Muscle Nerve 2011     

Effects of moderate‐ and high‐intensity chronic exercise on brain‐derived neurotrophic factor expression in fast and slow muscles

Introduction: Brain‐derived neurotrophic factor (BDNF) protein expression is sensitive to cellular activity. In the sedentary state, BDNF expression is affected by the muscle phenotype. Methods: Eighteen Wistar rats were divided into the following 3 groups: sedentary (S); moderate‐intensity training (MIT); and high‐intensity training (HIT). The training protocol lasted 8 weeks. Forty‐eight hours after training, total RNA and protein levels in the soleus and plantaris muscles were obtained. Results: In the plantaris, the BDNF protein level was lower in the HIT than in the S group (P < 0.05). A similar effect was found in the soleus (without significant difference). In the soleus, higher Bdnf mRNA levels were found in the HIT group (P < 0.001 vs. S and MIT groups). In the plantaris muscle, similar Bdnf mRNA levels were found in all groups. Conclusions: These results indicate that high‐intensity chronic exercise reduces BDNF protein level in fast muscles and increases Bdnf mRNA levels in slow muscles. Muscle Nerve 53: 446–451, 2016     

Activity attenuates skeletal muscle fiber damage after ischemia and reperfusion

Introduction: In this investigation we aimed to determine whether: (1) physical activity protects rat skeletal muscle from ischemia/reperfusion (I/R) injury; and (2) continued activity after I/R improves the rate of healing. Methods: Rats were divided into sedentary or active (voluntary wheel running) groups. Active rats ran for 4 weeks before I/R or 4 weeks before plus 4 weeks after I/R. Results: Activity before I/R resulted in 73.2% less muscle damage (Evans blue dye inclusion). Sedentary and active rats had a similar decline in neural‐evoked (～99%) and directly stimulated (～70%) in vivo muscle torque, and a similar reduction in junctophilin 1. Active rats produced 19% and 15% greater neural‐evoked torque compared with sedentary rats at 14 and 28 days postinjury, respectively, although the rate of recovery appeared similar. Conclusions: Activity protects against long‐term muscle damage, but not short‐term neural injury or excitation‐contraction uncoupling. Continued activity neither accelerates nor hinders the rate of functional recovery. Muscle Nerve 52: 640–648, 2015     

Outcome of intracerebral haemorrhage patients pre‐treated with statins

Background: Statins treatment may have potential clinical impact in vascular disease beyond cholesterol lowering. Its benefits have been documented in cerebral ischaemia and in subarachnoid haemorrhage. In intracerebral haemorrhage (ICH), experimental models in statin‐treated animals have better outcome than non‐treated ones, but in humans the relationship is unclear. We investigated whether patients treated with statins before the onset of intracerebral haemorrhage have a better outcome at 3 months than patients without statins pre‐treatment. Methods: Retrospective review of primary intracerebral haemorrhage case series from a prospective stroke register. We recorded demographics, vascular risk factors, previous statin treatment, Glasgow coma scale (GCS) at onset, ICH scale, hematoma volume and location, ventricular extension of the hematoma, and functional outcome at 3 months. The effect of prior statin treatment on good outcome (modified Rankin scale [mRS] 0 to 2) was analysed by logistic regression analysis. Results: We included 269 patients (age 71.9 ± 12.4, mean ± SD, 152 males). Thirty‐four patients (12.6%) were on prior statin treatment when admitted. There were no differences in fasting serum cholesterol and triglycerides levels between the statin pre‐treated groups and the group without statin pre‐treatment. Multivariate regression analysis showed a significant association between age (OR: 0.95; CI 0.92–0.97), ICH volume (OR: 0.96; CI 0.94–0.98), GCS (OR: 1.55; CI 1.21–1.98), pre‐treatment with statins (OR: 4.21; CI 1.47–12.17; P = 0.008), and good outcome at 3 months. Conclusions: Statins pre‐treatment of patients with intracerebral haemorrhage may provide better functional outcome at 3 months of acute onset.     

Aerobic training in patients with anoctamin 5 myopathy and hyperckemia

Introduction: Anoctamin 5 deficiency has recently been defined to cause limb‐girdle muscular dystrophy type 2L (LGMD2L) with pronounced hyperCKemia. No treatment interventions have been made so far in this condition. Methods: In 6 patients with LGMD2L, we studied the effect of home‐based, pulse‐watch monitored, moderate‐intensity exercise on a cycle ergometer for 30 minutes, 3 times weekly, for 10 weeks. Plasma creatine kinase (CK) was assessed before, during, and after the program as a marker of muscle damage. Primary outcome measures were maximum oxygen uptake (VO_2max) and time in the 5‐repetitions‐sit‐to‐stand test (FRSTST). Results: Training resulted in improvements in VO_2max (27 ± 7%; P = 0.0001) and FRSTST time (35 ± 12%; P = 0.007). Improvements in physiologic and functional muscle testing were accompanied by stable CK levels and no reports of adverse effects. Conclusions: These findings suggest that supervised aerobic exercise training is safe and effective in improving oxidative capacity and muscle function in patients with anoctamin 5 deficiency. Muscle Nerve 50 : 119–123, 2014     

Clinical and genetic associations of autoantibodies to 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme a reductase in patients with immune‐mediated myositis and necrotizing myopathy

Introduction: Inhibition of 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune‐mediated necrotizing myopathy (IMNM). Anti‐HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti‐HMGCR in IIM/IMNM. Methods: Anti‐HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. Results: Anti‐HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti‐HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA‐DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti‐HMGCR antibodies was among HLA‐DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti‐HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti‐HMGCR⁺ patients there was a trend toward increased malignancy (P = 0.15). Conclusions: Anti‐HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA‐DR11. Muscle Nerve 52 : 196–203, 2015     

Selectively reshaping a muscle phenotype: functional overload of cat plantaris

Introduction: Functional overload (FO) of the fast plantaris muscle was studied in treadmill‐exercised (FO‐Ex) or sedentary (FO‐Sed) adult cats. Methods: Mechanical, phenotype, and kinematics analyses were performed. Results: Plantigrade vs. normal digitigrade posture was observed early post‐FO. Relative plantaris mass was greater in FO‐Sed (10%) and FO‐Ex (60%) cats than in controls 12 weeks post‐FO. Specific tension was similar across groups, indicating functional hypertrophy. Fiber size was greater, percent slow fibers higher, percent IIa myosin heavy chain (MHC) higher, and IIx MHC lower in FO‐Ex than controls. Twitch and half‐relaxation times were longer, and the frequency–tension curve shifted toward that observed in slow muscles. Electromyography (EMG) and tendon force amplitudes during stepping were larger, and the yield (lengthening) phase occurred at a longer muscle length before compared with after FO. Discussion: Reshaping the plantaris phenotype was highly dependent on the overload stimulus, indicating that electrical stimulation paradigms used during rehabilitation should be performed with the muscles under “loaded” conditions. Muscle Nerve, 2011     

Muscle function in monozygotic female twin pairs discordant for hormone replacement therapy

Introduction: Postmenopausal monozygotic twin pairs discordant for hormone replacement therapy (HRT) provide an advantageous study design controlling for genetic background for elucidating the relationships between aging, sex hormone levels, muscle strength, contractile capacity, and fatigability. Methods: Thirteen postmenopausal monozygotic twin pairs discordant for HRT were measured for maximal voluntary torque (MVC) and twitch characteristics using electrical stimulation before and after intermittent dynamic plantarflexor exercise until exhaustion. Results: Peak twitch torque was 32% higher in HRT users than in their non‐HRT, genetically identical sisters (P = 0.002), but MVC did not differ. There were no differences in the activation level or twitch time characteristics between the co‐twins. Fatigue caused decreases in MVC (P = 0.001), twitch torque (P = 0.001), time to peak (P = 0.013), and half‐relaxation time (P = 0.001) similarly in HRT users and non–HRT users. Conclusion: In early postmenopausal women, involuntary but not voluntary force‐generating mechanisms of the plantarflexors are augmented by the use of HRT. Muscle Nerve, 2011     

Platelet‐rich plasma limits the nerve injury caused by 10% dextrose in the rabbit median nerve

Introduction: We evaluated the effect of platelet‐rich plasma (PRP) injection in a rabbit model of dextrose‐induced median nerve injury. Methods: New Zealand white rabbits (n = 15) were divided randomly into 3 groups. Three different regimens (group 1: 0.1 ml saline; group 2: 10% dextrose with PRP; group 3: 10% dextrose with saline) were injected within the carpal tunnel. Electrophysiological and histological findings were evaluated 12 weeks after the injection. Results: The mean median motor latency in group 3 was significantly longer than that in groups 1 and 2. The cross‐sectional area of the median nerve and subsynovial connective tissue thickness in group 3 were significantly larger than those in groups 1 and 2. Conclusions: PRP injection may be effective in controlling median nerve injury, as demonstrated by improvement in electrophysiological and histological findings 12 weeks after dextrose injection. Muscle Nerve 49 : 56–60, 2014