The wasting-associated oncometabolite succinate disrupts myogenesis and impairs skeletal muscle regeneration

Paige C. Arneson, Kelly A. Hogan, Alexandra M. Shin, Adrienne Samani, Aminah Jatoi, Jason Doles

Research output: Contribution to journalArticlepeer-review

Abstract

Background Loss of muscle mass and function are major clinical phenomena affecting most advanced cancer patients. Recent work shows that defects in muscle regeneration contribute to cancer-associated wasting. Among the factors implicated in wasting-associated suppression of muscle regeneration are cytokines that interfere with myogenic signal transduction pathways. Less understood is how other cancer/wasting-associated cues, such as oncometabolites, contribute to muscle dysfunction. This study investigates how the oncometabolite succinate affects myogenesis and muscle regeneration. Methods We leveraged an established ectopic metabolite treatment strategy to evaluate the ability of intracellular succinate elevation to 1) affect myoblast homeostasis (growth/proliferation, apoptosis), 2) stimulate wasting-associated catabolism, and 3) modulate in vitro myogenesis. In vivo succinate supplementation experiments were utilized to corroborate and extend in vitro observations. Metabolic studies were then performed to investigate the impact of succinate elevation on mitochondria function. Results We found that in vitro succinate elevation in myoblasts interferes with protein homeostasis and myogenic differentiation. Mice orally administered succinate displayed smaller muscle myofiber diameters and exhibited impaired skeletal muscle regeneration when challenged with barium chloride-induced muscle injury. Finally, we found that succinate elevation was associated with functional mitochondria deficits. Conclusions Overall, this study broadens the repertoire of wasting-associated factors that can directly modulate muscle progenitor cell function and strengthens the hypothesis that metabolic derangements are major contributors to cancer-associated muscle wasting.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Oct 29 2019

Keywords

  • Muscle wasting
  • Myogenesis
  • Skeletal muscle
  • Succinate

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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