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

Publication date: Available online 5 April 2018
Source:Cell Metabolism
Author(s): Stas Wüst, Stefan Dröse, Juliana Heidler, Ilka Wittig, Ina Klockner, Andras Franko, Erik Bonke, Stefan Günther, Ulrich Gärtner, Thomas Boettger, Thomas Braun
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.

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Teaser

Wüst et al. identified a regulatory axis consisting of miR-1/133a, the transcription factor MEF2A, and miRNAs located within the Dlk1-Dio3 gene cluster, critical for normal mitochondrial morphology and function in skeletal muscles. Axis disruption prevents activation of efficient mitochondrial respiration after muscle stem cell differentiation and lasting muscle activity.


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