Skeletal muscle injuries occur frequently in daily life and exercise. Understanding the mechanisms of regeneration is critical for accelerating the repair and regeneration of muscle. Therefore, this article reviews knowledge on the mechanisms of skeletal muscle regeneration after cardiotoxin-induced injury. The process of regeneration is similar in different mouse strains and is inhibited by aging, obesity, and diabetes. Exercise, microcurrent electrical neuromuscular stimulation, and mechanical loading improve regeneration. The mechanisms of regeneration are complex and strain-dependent, and changes in functional proteins involved in the processes of necrotic fiber debris clearance, M1 to M2 macrophage conversion, SC activation, myoblast proliferation, differentiation and fusion, and fibrosis and calcification influence the final outcome of the regenerative activity.

Cystathionine-γ-lyase (CSE) is expressed in various tissues and generates H2S via an alternative desulfuration reaction. We sought to explore the functions of skeletal muscle CSE using skeletal muscle conditional knockout CSE (MCSEKO) mice. It was found that body weight, muscle morphology, and exercise capacity were not altered in MCSEKO mice compared with littermate wild-type mice. RNA-seq-based transcriptome analysis showed that 275 genes were differentially regulated in skeletal muscle and multiple signaling pathways including insulin signaling and mTOR, PI3K-AKT, and cGMP-PKG signaling pathways were enriched in MCSEKO mice. The intraperitoneal glucose tolerance test and insulin tolerance test showed that glucose tolerance and insulin sensitivity were reduced in MCSEKO mice. Glucose transporter 4 (GLU4) and PKG-1 expression levels and insulin receptor substrate-1(IRS1)/PI3K/Akt signaling pathway were downregulated whilst the mTOR/S6K/S6 pathway was enhanced in MCSEKO mice. These effects were reversed by the H2S supplement. Aerobic treadmill training significantly promoted glucose tolerance and insulin sensitivity and improved GLU4 and PKG-1 levels, promoted IRS1/PI3K/Akt signaling and suppressed mTOR/S6K/S6 signaling pathway in MCSEKO mice. Our data suggest that skeletal muscle CSE/H2S signaling is critical for the maintenance of insulin sensitivity, which is associated with maintaining the balance in PKG, PI3K/Akt, and mTOR/S6K/S6 signaling pathways in skeletal muscle.

Neuronal apoptosis has been well-recognized as a critical mediator in the pathogenesis of depressive disorders. Tissue kallikrein-related peptidase 8 (KLK8), a trypsin-like serine protease, has been implicated in the pathogenesis of several psychiatric disorders. The present study aimed to explore the potential function of KLK8 in hippocampal neuronal cell apoptosis associated with depressive disorders in rodent models of chronic unpredictable mild stress (CUMS)-induced depression. It was found that depression-like behavior in CUMS-induced mice was associated with hippocampal KLK8 upregulation. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency attenuated CUMS-induced depression-like behaviors and hippocampal neuronal apoptosis. In HT22 murine hippocampal neuronal cells and primary hippocampal neurons, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce neuron apoptosis. Mechanistically, it was identified that the neural cell adhesion molecule 1 (NCAM1) may associate with KLK8 in hippocampal neurons as KLK8 proteolytically cleaved the NCAM1 extracellular domain. Immunofluorescent staining exhibited decreased NCAM1 in hippocampal sections obtained from mice or rats exposed to CUMS. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency largely prevented CUMS-induced loss of NCAM1 in the hippocampus. Both adenovirus-mediated overexpression of NCAM1 and NCAM1 mimetic peptide rescued KLK8-overexpressed neuron cells from apoptosis. Collectively, this study identified a new pro-apoptotic mechanism in the hippocampus during the pathogenesis of CUMS-induced depression via the upregulation of KLK8, and raised the possibility of KLK8 as a potential therapeutic target for depression.