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Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Aug 01; Vol. 114 (31), pp. 8402-8407. Date of Electronic Publication: 2017 Jul 17. - Publication Year :
- 2017
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Abstract
- 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 O <subscript>2</subscript> 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.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Adolescent
Adult
Aged
Citric Acid Cycle genetics
Electron Transport physiology
Female
Glycogen metabolism
Glycogen Storage Disease Type V genetics
Heart Rate physiology
Humans
Male
Metabolome physiology
Middle Aged
Mitochondria metabolism
Mitochondrial Myopathies genetics
Muscle, Skeletal metabolism
Oxidative Phosphorylation
Oxygen Consumption physiology
Triglycerides metabolism
Young Adult
Citric Acid Cycle physiology
Energy Metabolism physiology
Exercise physiology
Glycogen Storage Disease Type V pathology
Mitochondrial Myopathies pathology
Muscle, Skeletal pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 114
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 28716914
- Full Text :
- https://doi.org/10.1073/pnas.1703338114