Ronald Gerald Haller

McArdle disease and mitochondrial myopathy impair muscle oxidative phosphorylation (OXPHOS) by distinct mechanisms: the former by restricting oxidative substrate availability caused by blocked glycogen breakdown, the latter because of intrinsic respiratory chain defects. We applied metabolic profiling to systematically interrogate these disorders at rest, when muscle symptoms are typically minimal, and with exercise, when symptoms of premature fatigue and potential muscle injury are unmasked. At rest, patients with mitochondrial disease exhibit elevated lactate and reduced uridine; in McArdle disease purine nucleotide metabolites, including xanthine, hypoxanthine, and inosine are elevated. During exercise, glycolytic intermediates, TCA cycle intermediates, and pantothenate expand dramatically in both mitochondrial disease and control subjects. In contrast, in McArdle disease, these metabolites remain unchanged from rest; but urea cycle intermediates are increased, likely attributable to increased ammonia production as a result of exaggerated purine degradation. Our results establish skeletal muscle glycogen as the source of TCA cycle expansion that normally accompanies exercise and imply that impaired TCA cycle flux is a central mechanism of restricted oxidative capacity in this disorder. Finally, we report that resting levels of long-chain triacylglycerols in mitochondrial myopathy correlate with the severity of OXPHOS dysfunction, as indicated by the level of impaired O₂ extraction from arterial blood during peak exercise. Our integrated analysis of exercise and metabolism provides unique insights into the biochemical basis of these muscle oxidative defects, with potential implications for their clinical management. Significance Metabolic myopathies resulting from defects in skeletal muscle energy metabolism represent a spectrum of disorders that are typically mild at rest and unmasked with exercise. Although the genetic basis for many metabolic myopathies is known, their management remains challenging in part because we have an incomplete understanding of the biochemical pathogenesis. Here we applied plasma metabolic profiling to capture a holistic picture of metabolism at rest and with exercise in two metabolic myopathies that restrict oxidative metabolism: McArdle disease, characterized by defective glycogen fuel mobilization, and mitochondrial disease, characterized by a defective respiratory chain. Our work provides insights into how biochemistry is remodeled in these two disorders, revealing candidate biomarkers that may prove to have clinical utility.

Human skeletal muscle respiratory chain defects restrict the ability of working muscle to extract oxygen from blood, and result in a hyperkinetic circulation during exercise in which oxygen delivery is excessive relative to oxygen uptake and oxygen levels within contracting muscle are abnormally high. To investigate the role of the muscle microcirculation in this anomalous circulatory response and possible implications for the regulation of muscle angiogenesis, we assessed muscle oxidative capacity during cycle exercise and determined capillary levels and distribution and vascular endothelial growth factor expression in quadriceps muscle biopsies in patients with mitochondrial myopathy attributable to heteroplasmic mitochondrial DNA mutations. We found that in patients with mitochondrial myopathy, muscle capillary levels were twice that of sedentary healthy subjects (3.0 ± 0.9% compared with 1.4 ± 0.3%, P < 0.001) despite the fact that oxygen utilization during peak cycle exercise was half that of control subjects (11.1 ± 4.0 ml/kg/min compared with 20.7 ± 7.9 ml/kg/min, P < 0.01); that capillary area was greatest in patients with the most severe muscle oxidative defects and was more than two times higher around muscle fibre segments with defective (i.e. cytochrome oxidase negative/succinic dehydrogenase-positive or 'ragged-red' fibres) compared with more preserved respiratory chain function; and that vascular endothelial growth factor expression paralleled capillary distribution. The increased muscle capillary levels in patients correlated directly (r(2) = 0.68, P < 0.05) with the severity of the mismatch between systemic oxygen delivery (cardiac output) and oxygen utilization during cycle exercise. Our results suggest that capillary growth is increased as a result of impaired muscle oxidative phosphorylation in mitochondrial myopathy, thus promoting increased blood flow to respiration-incompetent muscle fibres and a mismatch between oxygen delivery and utilization during exercise. Furthermore, the finding of high capillary levels despite elevated tissue oxygen levels during exercise in respiration-deficient muscle fibres implies that mitochondrial metabolism activates angiogenesis in skeletal muscle by a mechanism that is independent of hypoxia.

Huntington disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in humans and animal models. Here we review the clinical, biochemical, and molecular evidence of an energy deficit in HD and discuss the mechanisms underlying mitochondrial and related alterations.

Objective: Susceptibility to exertional cramps and rhabdomyolysis in myophosphorylase deficiency (McArdle's disease [MD]) may lead patients to shun exercise. However, physical inactivity may worsen exercise intolerance by further reducing the limited oxidative capacity caused by blocked glycogenolysis. We investigated whether aerobic conditioning can safely improve exercise capacity in MD.Methods: Eight MD patients (4 men and 4 women; age range, 33–61 years) pedaled a cycle ergometer for 30 to 40 minutes a day, 4 days a week, for 14 weeks, at an intensity corresponding to 60 to 70% of maximal heart rate. We monitored serum creatine kinase levels; changes in peak cycle work, oxygen uptake, and cardiac output; presence and magnitude of a spontaneous and glucose‐induced second wind; and citrate synthase and β‐hydroxyacyl coenzyme A dehydrogenase enzyme activities in quadriceps muscle.Results: The prescribed exercise program increased average work capacity (36%), oxygen uptake (14%), cardiac output (15%), and citrate synthase and β‐hydroxyacyl coenzyme A dehydrogenase enzyme levels (80 and 62%, respectively) without causing pain or cramping or increasing serum creatine kinase. A spontaneous and glucose‐induced second wind was present and was of similar magnitude in each patient before and after training.Interpretation: Moderate aerobic exercise is an effective means of improving exercise capacity in MD by increasing circulatory delivery and mitochondrial metabolism of bloodborne fuels. Ann Neurol 2006;59:922‐928

A cardinal feature of impaired skeletal muscle oxidative metabolism in mitochondrial myopathies is a limited ability to increase the extraction of O₂ from blood relative to the increase in O₂ delivery by the circulation during exercise. We investigated whether aerobic forearm exercise would result in an abnormal increase in venous effluent O₂ in patients with impaired skeletal muscle oxidative phosphorylation attributable to mitochondrial disease. We monitored the partial pressure of O₂ (PO₂) in cubital venous blood at rest, during handgrip exercise, and during recovery in 13 patients with mitochondrial myopathy and exercise intolerance and in 13 healthy control and 11 patient control subjects. Resting and recovery venous effluent PO₂ were similar in all subjects, but during exercise venous PO₂ paradoxically rose in mitochondrial myopathy patients from 27.2 ± 4.0mmHg to 38.2 ± 13.3mmHg, whereas PO₂ fell from 27.2 ± 4.2mmHg to 24.2 ± 2.7mmHg in healthy subjects and from 27.4 ± 9.5mmHg to 22.2 ± 5.2mmHg in patient controls. The range of elevated venous PO₂ during forearm exercise in mitochondrial myopathy patients (32 to 82mmHg) correlated closely with the severity of oxidative impairment as assessed during cycle exercise. We conclude that measurement of venous PO₂ during aerobic forearm exercise provides an easily performed screening test that sensitively detects impaired O₂ use and accurately assesses the severity of oxidative impairment in patients with mitochondrial myopathy and exercise intolerance.