PT  - JOURNAL ARTICLE
AU  - Akihiro Ikenaka
AU  - Yohko Kitagawa
AU  - Michiko Yoshida
AU  - Chuang-Yu Lin
AU  - Akira Niwa
AU  - Tatsutoshi Nakahata
AU  - Megumu K Saito
TI  - SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis
AID  - 10.26508/lsa.202201457
DP  - 2023 Mar 01
TA  - Life Science Alliance
PG  - e202201457
VI  - 6
IP  - 3
4099  - https://www.life-science-alliance.org/content/6/3/e202201457.short
4100  - https://www.life-science-alliance.org/content/6/3/e202201457.full
SO  - Life Sci. Alliance2023 Mar 01; 6
AB  - 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.