title: Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy.
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.
authors.affiliation: The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190;
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Reyes
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195;
authors.forename: Glen B
authors.initials: GB
authors.lastname: Banks
authors.affiliation: The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190;
authors.forename: Mark
authors.initials: M
authors.lastname: Tsang
authors.affiliation: Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024;
authors.forename: Daciana
authors.initials: D
authors.lastname: Margineantu
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, Northwest Metabolomics Research Center, University of Washington, Seattle, WA 98109-8057; and.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, Northwest Metabolomics Research Center, University of Washington, Seattle, WA 98109-8057; and.
authors.forename: Danijel
authors.initials: D
authors.lastname: Djukovic
authors.affiliation: The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190;
authors.forename: Jacky
authors.initials: J
authors.lastname: Chan
authors.affiliation: The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190;
authors.forename: Michelle
authors.initials: M
authors.lastname: Torres
authors.affiliation: The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190;
authors.forename: H Denny
authors.initials: HD
authors.lastname: Liggitt
authors.affiliation: The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190;
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Hirenallur-S
authors.affiliation: Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024;
authors.forename: David M
authors.initials: DM
authors.lastname: Hockenbery
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, Northwest Metabolomics Research Center, University of Washington, Seattle, WA 98109-8057; and Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024.
authors.forename: Daniel
authors.initials: D
authors.lastname: Raftery
authors.affiliation: The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190; biritani@uw.edu.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Iritani
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D009119:Muscle Contraction / Q000502:physiology; D018763:Muscle Fatigue / Q000502:physiology; D018656:Muscle Fibers, Fast-Twitch / Q000473:pathology* / Q000502:physiology*; D018657:Muscle Fibers, Slow-Twitch / Q000473:pathology* / Q000502:physiology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009211:Myoglobin / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C581709:FNIP1 protein, mouse; D046912:Multiprotein Complexes; C551613:Myh7 protein, mouse; D009211:Myoglobin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D018995:Myosin Heavy Chains
keywords: AMPK; BHD; PGC1α; folliculin; mTOR