Lipid-lowering drugs produce myopathic side effects in up to 7% of treated patients, with severe rhabdomyolysis occurring in as many as 0.5%. Underlying metabolic muscle diseases have not been evaluated extensively. In a cross-sectional study of 136 patients with drug-induced myopathies, we report a higher prevalence of underlying metabolic muscle diseases than expected in the general population. Control groups included 116 patients on therapy with no myopathic symptoms, 100 asymptomatic individuals from the general population never exposed to statins, and 106 patients with non-statin-induced myopathies. Of 110 patients who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing three metabolic myopathies, compared to 3% testing positive among asymptomatic patients on therapy (P = 0.04). The actual number of mutant alleles found in the test group patients was increased fourfold over the control group (P < 0.0001) due to an increased presence of mutation homozygotes. The number of carriers for carnitine palmitoyltransferase II deficiency and for McArdle disease was increased 13- and 20-fold, respectively, over expected general population frequencies. Homozygotes for myoadenylate deaminase deficiency were increased 3.25-fold with no increase in carrier status. In 52% of muscle biopsies from patients, significant biochemical abnormalities were found in mitochondrial or fatty acid metabolism, with 31% having multiple defects. Variable persistent symptoms occurred in 68% of patients despite cessation of therapy. The effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high-risk groups.

There is no generally effective therapy for mitochondrial myopathies. In this study, we measured responses to combined aerobic training and oral dichloroacetate (DCA) therapy in a 25-year-old woman with a mitochondrial myopathy caused by cytochrome oxidase deficiency. The patient trained for 14 weeks, and DCA therapy was begun after 8 weeks. Independent indices of aerobic capacity and oxidative metabolism showed substantial improvement. Venous lactate concentrations at rest, and after a constant amount of work, decreased by approximately 50% after 8 weeks of aerobic training, and by more than 70% with the combination of training and DCA treatment. Heart rate at rest and after a constant amount of submaximal work decreased progressively. Aerobic capacity on a graded submaximal exercise test improved by 71% from baseline by the end of the treatment period. 31P magnetic resonance spectroscopy measurements of rate constants for recovery of muscle phosphocreatine increased 1.7-fold and metabolically active adenine diphosphate increased 2.8-fold after 8 weeks of training alone, and 4.5-fold and 23.0-fold after 14 weeks of training plus DCA treatment. Responses to the SF-36 Health Survey suggested a marked reduction in handicap. Thus, in this open study of a patient with cytochrome oxidase deficiency, a combination of aerobic training and DCA treatment resulted in substantial improvements in biochemical indices, exercise performance, and handicap. We conclude that exercise limitation in patients with mitochondrial myopathy may arise from effects of chronic deconditioning in addition to the effects of primary mitochondrial dysfunction and may be partially reversed by training and administration of DCA.

Introduction Of nearly 38 million people in the U.S. receiving statin therapy, 0.1–0.5% experience severe or life-threatening myopathic side effects. Methods We performed a genome-wide association study (GWAS) in patients with severe statin myopathy versus a statin-tolerant group to identify genetic susceptibility loci. Results Replication studies in independent groups of severe statin myopathy (n=190) and statintolerant controls (n=130) resulted in the identification of three SNPs, rs9342288, rs1337512 and rs3857532, in the eyes shut homolog (EYS) on chromosome 6 suggestive of an association with risk for severe statin myopathy (p=0.0003–0.0008). Analysis of EYS cDNA demonstrated that EYS gene products are complex and expressed with relative abundance in the spinal cord as well as in the retina. Discussion Structural similarities of these EYS gene products to members of the Notch signaling pathway and to agrin suggest a possible functional role in the maintenance and regeneration of the structural integrity of skeletal muscle.

Methods for measuring mitochondrial activity from 31P magnetic resonance spectroscopy data collected during and after exercise were compared in controls, weight lifters, and peripheral vascular occlusive disease (PVOD) patients. There were trends toward increasing mitochondrial activity during exercise in order from PVOD patients, moderately active controls, highly active controls, to weight lifters. Results from PVOD patients show divergence of some measures due to 1) the non‐exponential nature of phosphocreatine recovery, and 2) potential breakdown of [ADP] control of the mitochondria due to lack of oxygen (for Qmax calculation). These results demonstrate the utility of obtaining and directly analyzing high time resolution data rather than assuming monoexponential behavior of metabolite recovery. Magn Reson Med 41:1145–1151, 1999. © 1999 Wiley‐Liss, Inc.