Metabolic Maturation during Muscle Stem Cell Differentiation Is Achieved by miR-1/133a-Mediated Inhibition of the Dlk1-Dio3 Mega Gene Cluster

Cell Metab. 2018 May 1;27(5):1026-1039.e6. doi: 10.1016/j.cmet.2018.02.022. Epub 2018 Apr 5.

Abstract

Muscle stem cells undergo a dramatic metabolic switch to oxidative phosphorylation during differentiation, which is achieved by massively increased mitochondrial activity. Since expression of the muscle-specific miR-1/133a gene cluster correlates with increased mitochondrial activity during muscle stem cell (MuSC) differentiation, we examined the potential role of miR-1/133a in metabolic maturation of skeletal muscles in mice. We found that miR-1/133a downregulate Mef2A in differentiated myocytes, thereby suppressing the Dlk1-Dio3 gene cluster, which encodes multiple microRNAs inhibiting expression of mitochondrial genes. Loss of miR-1/133a in skeletal muscles or increased Mef2A expression causes continuous high-level expression of the Dlk1-Dio3 gene cluster, compromising mitochondrial function. Failure to terminate the stem cell-like metabolic program characterized by high-level Dlk1-Dio3 gene cluster expression initiates profound changes in muscle physiology, essentially abrogating endurance running. Our results suggest a major role of miR-1/133a in metabolic maturation of skeletal muscles but exclude major functions in muscle development and MuSC maintenance.

Keywords: Dlk1-Dio3; Mef2A; miR-1; miR-133a; microRNA; skeletal muscle metabolism; skeletal muscle mitochondria; skeletal muscle stem cells.

MeSH terms

  • Animals
  • Calcium-Binding Proteins
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Iodide Peroxidase / genetics*
  • MEF2 Transcription Factors / genetics
  • Mice
  • MicroRNAs / genetics*
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Multigene Family
  • Muscle Development / genetics
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle, Skeletal / metabolism*

Substances

  • Calcium-Binding Proteins
  • Dlk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • MEF2 Transcription Factors
  • Mef2a protein, mouse
  • MicroRNAs
  • Mirn1 microRNA, mouse
  • Mirn133 microRNA, mouse
  • iodothyronine deiodinase type III
  • Iodide Peroxidase