Dystrophinopathy-associated dysfunction of Krebs cycle metabolism

Angus Lindsay, Christopher M. Chamberlain, Bruce A. Witthuhn, Dawn A. Lowe, James M. Ervasti

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Duchenne muscular dystrophy is a deadly muscle-wasting disorder caused by loss of dystrophin protein. Studies suggest that metabolic alterations are important to disease pathogenesis. Because muscle accounts for ?40% of body mass, we hypothesized that dystrophy-mediated metabolic changes would be measurable in biofluids and that a metabolomic analysis of urine would provide insight into the metabolic status of dystrophic muscle. Using the mdx mouse model, we performed a large-scale metabolomic screen at 1 and 3 months. While 10% of metabolites were altered at age 1 month, 40% were changed at 3 months. Principal component analysis distinguished wild-type from mdx animals, with the greatest separation at 3 months. A critical distinguishing pathway was Krebs cycle metabolite depletion in mdx urine. Five of seven detected Krebs cycle metabolites were depleted in mdx urine, with succinate being the most robustly affected metabolite. Using selected reaction monitoring mass spectrometry, we demonstrated that muscle-specific dystrophin expression corrects mdx succinate depletion. When subjected to downhill treadmill running, wild-type and mdx mice expressing recombinant dystrophin in skeletal muscle displayed significant increases in urinary succinate levels. However, mdx succinate levels were unchanged, suggesting urinary succinate depletion may ref lect an inability to upregulate the Krebs cycle following exercise. Finally, we show that supplementing the Krebs cycle in an ex vivo fatigue/recovery assay significantly impacts mdx muscle performance but has no effect on wild-type muscle. Our results suggest that global metabolic impairment is associated with mdx disease progression and that Krebs cycle deficiencies are a downstream consequence of dystrophin loss.

Original languageEnglish (US)
Pages (from-to)942-951
Number of pages10
JournalHuman molecular genetics
Volume28
Issue number6
DOIs
StatePublished - Mar 15 2019

Bibliographical note

Funding Information:
Muscular Dystrophy Association (349549); University of Minnesota AHC Seed Grant; gifts from John and Cheryl Gunvalson and the Gregory Marzolf Jr. Foundation; National Institutes of Health (RO1 AR042423 and RO1 AR049899).

Publisher Copyright:
© 2018 The Author(s).

Fingerprint

Dive into the research topics of 'Dystrophinopathy-associated dysfunction of Krebs cycle metabolism'. Together they form a unique fingerprint.

Cite this