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SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis.

ABSTRACT: Spinal muscular atrophy (SMA) is a congenital neuromuscular disease caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Although the primary cause of progressive muscle atrophy in SMA has classically been considered the degeneration of motor neurons, recent studies have indicated a skeletal muscle-specific pathological phenotype such as impaired mitochondrial function and enhanced cell death. Here, we found that the down-regulation of SMN causes mitochondrial dysfunction and subsequent cell death in in vitro models of skeletal myogenesis with both a murine C2C12 cell line and human induced pluripotent stem cells. During myogenesis, SMN binds to the upstream genomic regions of MYOD1 and microRNA (miR)-1 and miR-206. Accordingly, the loss of SMN down-regulates these miRs, whereas supplementation of the miRs recovers the mitochondrial function, cell survival, and myotube formation of SMN-deficient C2C12, indicating the SMN-miR axis is essential for myogenic metabolic maturation. In addition, the introduction of the miRs into ex vivo muscle stem cells derived from Δ7-SMA mice caused myotube formation and muscle contraction. In conclusion, our data revealed novel transcriptional roles of SMN during myogenesis, providing an alternative muscle-oriented therapeutic strategy for SMA patients.

SUBMITTER: Ikenaka A

PROVIDER: S-EPMC9834662 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis.

Ikenaka Akihiro A Kitagawa Yohko Y Yoshida Michiko M Lin Chuang-Yu CY Niwa Akira A Nakahata Tatsutoshi T Saito Megumu K MK

Life science alliance 20230105 3

Spinal muscular atrophy (SMA) is a congenital neuromuscular disease caused by the mutation or deletion of the <i>survival motor neuron 1 (SMN1)</i> gene. Although the primary cause of progressive muscle atrophy in SMA has classically been considered the degeneration of motor neurons, recent studies have indicated a skeletal muscle-specific pathological phenotype such as impaired mitochondrial function and enhanced cell death. Here, we found that the down-regulation of SMN causes mitochondrial dy ...[more]

PMID: 36604149

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SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis.

Publications

SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis.

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