Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration.

Mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c), a mitochondrial microprotein, has been described as a novel regulator of glucose and lipid metabolism. In addition to its role as a metabolic regulator, MOTS-c prevents skeletal muscle atrophy in high fat-fed mice. Here, we examined the preventive effect of MOTS-c on skeletal muscle mass, using an immobilization-induced muscle atrophy model, and explored its underlying mechanisms. Male C57BL/6J mice (10 wk old) were randomly assigned to one of the three experimental groups: nonimmobilization control group (sterilized water injection), immobilization control group (sterilized water injection), and immobilization and MOTS-c-treated group (15 mg/kg/day MOTS-c injection). We used casting tape for the immobilization experiment. After 8 days of the experimental period, skeletal muscle samples were collected and used for Western blotting, RNA sequencing, and lipid and collagen assays. Immobilization reduced ∼15% of muscle mass, whereas MOTS-c treatment attenuated muscle loss, with only a 5% reduction. MOTS-c treatment also normalized phospho-AKT, phospho-FOXO1, and phospho-FOXO3a expression levels and reduced circulating inflammatory cytokines, such as interleukin-1b (IL-1ß), interleukin-6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1), in immobilized mice. Unbiased RNA sequencing and its downstream analyses demonstrated that MOTS-c modified adipogenesis-modulating gene expression within the peroxisome proliferator-activated receptor (PPAR) pathway. Supporting this observation, muscle fatty acid levels were lower in the MOTS-c-treated group than in the casted control mice. These results suggest that MOTS-c treatment inhibits skeletal muscle lipid infiltration by regulating adipogenesis-related genes and prevents immobilization-induced muscle atrophy.NEW & NOTEWORTHY MOTS-c, a mitochondrial microprotein, attenuates immobilization-induced skeletal muscle atrophy. MOTS-c treatment improves systemic inflammation and skeletal muscle AKT/FOXOs signaling pathways. Furthermore, unbiased RNA sequencing and subsequent assays revealed that MOTS-c prevents lipid infiltration in skeletal muscle. Since lipid accumulation is one of the common pathologies among other skeletal muscle atrophies induced by aging, obesity, cancer cachexia, and denervation, MOTS-c treatment could be effective in other muscle atrophy models as well.

Sports activities at a young age decrease hypertension risk-The J-Fit+ study.

This study aimed to assess (1) blood pressure between young, current athletes, and non-athletes early in life; (2) hypertension prevalence between former athletes and the general population later in life; and (3) understand the mechanisms between exercise training and hypertension risks in the form of DNA methylation. Study 1: A total of 354 young male participants, including current athletes, underwent blood pressure assessment. Study 2: The prevalence of hypertension in 1269 male former athletes was compared with that in the Japanese general population. Current and former athletes were divided into three groups: endurance-, mixed-, and sprint/power-group. Study 3: We analyzed the effect of aerobic- or resistance-training on DNA methylation patterns using publicly available datasets to explore the possible underlying mechanisms. In young, current athletes, the mixed- and sprint/power-group exhibited higher systolic blood pressure, and all groups exhibited higher pulse pressure than non-athletes. In contrast, the prevalence of hypertension in former athletes was significantly lower in all groups than in the general population. Compared to endurance-group (reference), adjusted-hazard ratios for the incidence of hypertension among mixed- and sprint/power-group were 1.24 (0.87-1.84) and 1.50 (1.04-2.23), respectively. Moreover, aerobic- and resistance-training commonly modified over 3000 DNA methylation sites in skeletal muscle, and these were suggested to be associated with cardiovascular function-related pathways. These findings suggest that the high blood pressure induced by exercise training at a young age does not influence the development of future hypertension. Furthermore, previous exercise training experiences at a young age could decrease the risk of future hypertension.