Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy

Nicholas L. Reyes, Glen B. Banks, Mark Tsang, Daciana Margineantu, Haiwei Gu, Danijel Djukovic, Jacky Chan, Michelle Torres, H. Denny Liggitt, Dinesh K. Hirenallur-S, David M. Hockenbery, Daniel Raftery, Brian M. Iritani

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I red slow twitch and type II white fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases.

Original languageEnglish (US)
Pages (from-to)424-429
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number2
DOIs
StatePublished - Jan 13 2015

Keywords

  • AMPK
  • BHD
  • Folliculin
  • MTOR
  • PGC1α

ASJC Scopus subject areas

  • General

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    Reyes, N. L., Banks, G. B., Tsang, M., Margineantu, D., Gu, H., Djukovic, D., Chan, J., Torres, M., Liggitt, H. D., Hirenallur-S, D. K., Hockenbery, D. M., Raftery, D., & Iritani, B. M. (2015). Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America, 112(2), 424-429. https://doi.org/10.1073/pnas.1413021112