title: Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit.
abstract: Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative-type fibers. However, the mechanism for coupling of mitochondrial function to the muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR-208b/miR-499, parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR-499 drives a PGC-1α-dependent mitochondrial oxidative metabolism program to match shifts in slow-twitch muscle fiber composition. Mechanistically, miR-499 directly targets Fnip1, an AMP-activated protein kinase (AMPK)-interacting protein that negatively regulates AMPK, a known activator of PGC-1α. Inhibition of Fnip1 reactivated AMPK/PGC-1α signaling and mitochondrial function in myocytes. Restoration of the expression of miR-499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD Thus, we have identified a miR-499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function.
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Jing
authors: J
authors: Liu
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Xijun
authors: X
authors: Liang
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Danxia
authors: D
authors: Zhou
authors: Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA.
authors: Ling
authors: L
authors: Lai
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Liwei
authors: L
authors: Xiao
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Lin
authors: L
authors: Liu
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Tingting
authors: T
authors: Fu
authors: Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, China.
authors: Yan
authors: Y
authors: Kong
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Qian
authors: Q
authors: Zhou
authors: Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA.
authors: Rick B
authors: RB
authors: Vega
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Min-Sheng
authors: MS
authors: Zhu
authors: Diabetes and Obesity Research Center, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA.
authors: Daniel P
authors: DP
authors: Kelly
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
authors: Xiang
authors: X
authors: Gao
authors: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China ganzj@nju.edu.cn.
authors: Zhenji
authors: 0000-0001-5940-207X
authors: Z
authors: Gan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000222:Adaptation, Physiological; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000096:biosynthesis; D024462:Myosin Type II / Q000096:biosynthesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; C581709:FNIP1 protein, mouse; C573190:MIRN499 microRNA, mouse; D035683:MicroRNAs; C543978:Mirn208 microRNA, mouse; C483905:Myh14 protein, mouse; C551613:Myh7 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D055372:AMP-Activated Protein Kinases; D024462:Myosin Type II; D018995:Myosin Heavy Chains
keywords: contractile fiber type; gene regulation; microRNA; mitochondrial function; muscle