TY - JOUR
T1 - Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy
AU - Delaney, Nigel F.
AU - Sharma, Rohit
AU - Tadvalkar, Laura
AU - Clish, Clary B.
AU - Haller, Ronald G.
AU - Mootha, Vamsi K.
N1 - Funding Information:
We thank P. Wyrick, M. Newby, and P. Fowler for assistance in subject recruitment, exercise testing, and sample collection and A. Deik and A. Souza for technical assistance. This work was supported by the NIH Grants R01-AR050597 (to R.G.H.) and R01-DK081457 (to V.K.M.); the Muscular Dystrophy Association (R.G.H.); the Giant Tiger Foundation (R.G.H.); and the Marriott Mitochondrial Disorders Network (V.K.M.). V.K.M. is an Investigator of the Howard Hughes Medical Institute.
Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - Exercise physiology
KW - McArdle disease
KW - Metabolic profiling
KW - Mitochondria
KW - TCA expansion
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U2 - 10.1073/pnas.1703338114
DO - 10.1073/pnas.1703338114
M3 - Article
C2 - 28716914
AN - SCOPUS:85026506136
SN - 0027-8424
VL - 114
SP - 8402
EP - 8407
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -