SMN Protein Contributes to Skeletal Muscle Cell Maturation Via Caspase-3 and Akt Activation

Abstract

Background/Aim: In spinal muscular atrophy (SMA), systemic deficiency of survival motor neurons (SMN) caused by loss or mutation of SMN1 leads to SMA symptoms. SMA was, for a long time, considered as a selective motorneuron disease. However, accumulated evidence suggests that skeletal muscle cells are affected by low levels of SMN protein. The purpose of this study was to elucidate the function of SMN protein in skeletal cell differentiation and maturation. Materials and Methods: In SMNΔ7 mice, which exhibit a systemic reduction of SMN protein, muscle atrophy was evaluated. To direct the effect of SMN against muscle cells, SMN functions were examined by knockdown of SMN in mouse myoblasts cell line C2C12 using siRNA. Results: SMNΔ7 mice showed muscle atrophy accompanied by decreased both expression of a myogenesis marker and a proliferating marker. In SMN-knockdown myoblasts, early expression of myosin heavy chain and reduced multinuclear myotube formation were found. Decreased caspase-3 activity and reduced phosphorylation of Akt were observed at an early stage of differentiation in SMN-knockdown myoblasts. Conclusion: A critical role of SMN protein in muscle cell differentiation via caspase-3 and Akt activation was shown.

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

“…To understand the skeletal muscle-specific pathology, we examined Δ7-SMA mice on postnatal day 3 (P3), which is before the occurrence of motor neuronal deficits. The body weight of P3 Δ7-SMA mice was already decreased compared with WT, as previously reported ( Ando et al, 2020 ) ( Fig S6A ), indicating that skeletal muscle atrophy had already begun. The expression level of sarcomeric protein actinin Alpha 2 (ACTN2) also decreased in the tibialis anterior (TA), gastrocnemius (GA), and diaphragm of Δ7-SMA mice ( Fig 6A ), which is a hallmark of skeletal muscle atrophy ( Schiaffino et al, 2013 ).…”

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

“…To understand the skeletal muscle-specific pathology, we examined Δ7-SMA mice on postnatal day 3 (P3), which is prior to the occurrence of motor neuronal deficits. The body weight of P3 Δ7-SMA mice was already decreased compared to WT, as previously reported (Ando et al, 2020) ( Figure S6A ), indicating that skeletal muscle atrophy had already begun. The expression level of sarcomeric protein actinin Alpha 2 (ACTN2) also decreased in the tibialis anterior (TA), gastrocnemius (GA) and diaphragm of Δ7-SMA mice ( Figure 6A ), which is a hallmark of skeletal muscle atrophy (Schiaffino et al, 2013).…”

Transcriptome Analysis in a Primary Human Muscle Cell Differentiation Model for Myotonic Dystrophy Type 1

“…Survival motor neurons 1 and 2 (SMN1/2) are downregulated in both proliferating and differentiated muscle cells twofold. Deficiency of SMN1/2 is usually associated with spinal muscular atrophy; however, it was shown that low levels influence muscle differentiation and maturation through the AKT signalling pathway [65]. Similar involvements in proliferation, apoptosis and differentiation are known for many of the genes displayed in Figure 5.…”