Abstract
Vitamin D (VD) was reported to play protective roles in skeletal muscle. This study aimed to explore whether endoplasmic reticulum (ER) stress inhibition is associated with the protective effects of VD/VD receptor (VDR) signaling on skeletal muscle functions. C2C12 skeletal muscle cells were treated with palmitic acid (PA) and then incubated with different concentrations of 1,25-(OH)2-vitamin D3 (VD3), and we found that VD3 improved the impaired cell viability induced by PA and increased VDR expression in a dose-dependent manner. Then 100 nM VD3 treatment and VDR overexpression both ameliorated PA-induced ER stress, apoptosis, inflammation and glucose uptake inhibition in C2C12 myocytes. Furthermore, VDR knockdown reversed the protective effects of VD3 on C2C12 cell functions. Additionally, PA-treated C2C12 cells were treated with VD3 alone or together with AMPK signaling inhibitor Compound C. VD3 promoted phosphorylation of AMPK and SIRT1 expression, while Compound C reversed these effects and abolished the protective effects of VD3 in C2C12 cells. High-fat diet (HFD)-fed mice were treated with VD3, and VD3 alleviated skeletal muscle loss and insulin resistance in mice. In conclusion, VD inhibited AMPK/SIRT1-mediated ER stress by increasing VDR expression, and further ameliorated skeletal muscle loss and insulin resistance in mice.
Highlights
Skeletal muscle is the most abundant tissue in the human body, accounting for about 40% of total body weight and 50‐70% of total protein content
Cell Counting Kit-8 (CCK-8) assay indicated that C2C12 cell viability decreased obviously after palmitic acid (PA) treatment, and vitamin D3 (VD3) improved the impaired cell viability induced by PA in a dose-dependent manner, and its protective effect on cell viability was most obvious at a maximum concentration of 100 nM (Figure 1A)
We found that C2C12 cell viability (Figure 2A) was reduced and cell apoptosis (Figure 2B, C) was increased after PA treatment, while VD3 enhanced cell viability and attenuated cell apoptosis in C2C12 cells
Summary
Skeletal muscle is the most abundant tissue in the human body, accounting for about 40% of total body weight and 50‐70% of total protein content. Skeletal muscle mass is strictly dependent on the appropriate balance between protein degradation and synthesis, and its loss is associated with weakness, fatigue, and insulin resistance (Frontera & Ochala, 2015). Emerging evidence has indicated ER stress as a potential mechanism responsible for apoptosis, inflammation and insulin resistance in skeletal muscle. Enhanced ER stress is observed in skeletal muscle of pregnant women with gestational diabetes mellitus, which can regulate inflammation and insulin resistance in pregnant women (Liong & Lappas, 2016). Loss of T-type calcium channel function leads to terminal mitochondrial-related apoptosis in C2C12 myotubes and skeletal muscle by activating ER stress signaling (Chen et al, 2020). Current evidence has proposed that chemical inhibition of ER stress ameliorates inflammation insulin resistance in skeletal muscle.
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