Irisin alters D-galactose-induced apoptosis by increasing caveolin-1 expression in C2C12 myoblasts and skeletal muscle fibroblasts.

Muscle atrophy and skeletal muscle fibrosis are significant pathological manifestations of primary sarcopenia. The regulation of C2C12 myoblast and skeletal muscle fibroblast apoptosis is associated with these pathological changes. Previous studies have indicated that irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), can alleviate primary sarcopenia. However, the mechanisms of the effect of irisin in age-related apoptosis remain unknown. Our present research aimed to explore the effect of irisin and the underlying mechanism of D-galactose (D-gal)-induced apoptosis in skeletal muscle fibroblasts and C2C12 myoblasts. We found the opposite effects of D-gal on C2C12 myoblasts and fibroblasts. We also found that irisin suppressed C2C12 cell apoptosis and promoted fibroblast apoptosis. Mechanistically, irisin altered D-gal-induced apoptosis by increasing caveolin-1 expression. Taken together, these findings further demonstrated that irisin is a potential agent that can treat aged-relative muscle atrophy and fibrosis.

Bidirectional effect of uric acid on C2C12 myotubes and its partial mechanism.

AIM: To explore the effects and mechanisms of different concentrations of uric acid on skeletal muscle cells. METHODS: C2C12 myoblasts were differentiated into myotubes and then exposed to a medium containing uric acid (0 µM, 200 µM, 400 µM, 600 µM, 800 µM, 1000 µM, 1200 µM, 1400 µM). The myotube diameters were observed under light microscopy; the expressions of myosin heavy chain (MyHC), autophagy-related proteins (LC3BII/LC3BI, P62), cGAS, and p-Sting/Sting proteins were analyzed using Western blotting or immunoprecipitation; and oxidative stress and mitochondrial damage were evaluated using ROS, mtDNA and JC-1 assays. Cell viability was measured via CCK8 assay, and 1000-µM uric acid was selected for follow-up experiments. Furthermore, C2C12 myotubes were divided into a blank control group (Ctrl), a high-uric-acid group (HUA), and an HUA plus cGASn inhibitor group (HUA + RU.521). Then, the myotube diameter was observed, oxidative stress and mitochondrial damage were evaluated, and MyHC and autophagy-related protein expressions were analysed. RESULTS: C2C12 myotubes cultured in 400-µM uric acid medium had the greatest myotube diameter and the highest MyHC protein expression. At 1000-µM uric acid, the diameter and MyHC protein expression were significantly decreased, LCB3II/LCB3I expression was notably increased, and the level of p62 protein expression was considerably decreased. RU.521 partially alleviated the HUA-induced C2C12 myotubes changes. CONCLUSIONS: Uric acid bidirectionally affected C2C12 myotubes: 400-µΜ uric acid promoted myotube growth, while 1000-µΜ uric acid triggered myotube atrophy with increased autophagy. Inhibiting cGAS-Sting signaling attenuated HUA-induced C2C12 myotube autophagy and atrophy. Geriatr Gerontol Int 2024; 24: 430-439.

Environmental determinants and demographic influences on global urban microbiomes, antimicrobial resistance and pathogenicity.

Urban microbiome plays crucial roles in human health and are related to various diseases. The MetaSUB Consortium has conducted the most comprehensive global survey of urban microbiomes to date, profiling microbial taxa/functional genes across 60 cities worldwide. However, the influence of environmental/demographic factors on urban microbiome remains to be elucidated. We collected 35 environmental and demographic characteristics to examine their effects on global urban microbiome diversity/composition by PERMANOVA and regression models. PM10 concentration was the primary determinant factor positively associated with microbial α-diversity (observed species: p = 0.004, ß = 1.66, R2 = 0.46; Fisher's alpha: p = 0.005, ß = 0.68, R2 = 0.43), whereas GDP per capita was negatively associated (observed species: p = 0.046, ß = -0.70, R2 = 0.10; Fisher's alpha: p = 0.004, ß = -0.34, R2 = 0.22). The ß-diversity of urban microbiome was shaped by seven environmental characteristics, including Köppen climate type, vegetation type, greenness fraction, soil type, PM2.5 concentration, annual average precipitation and temperature (PERMANOVA, p < 0.001, R2 = 0.01-0.06), cumulatively accounted for 20.3% of the microbial community variance. Canonical correspondence analysis (CCA) identified microbial species most strongly associated with environmental characteristic variation. Cities in East Asia with higher precipitation showed an increased abundance of Corynebacterium metruchotii, and cities in America with a higher greenness fraction exhibited a higher abundance of Corynebacterium casei. The prevalence of antimicrobial resistance (AMR) genes were negatively associated with GDP per capita and positively associated with solar radiation (p < 0.005). Total pathogens prevalence was positively associated with urban population and negatively associated with average temperature in June (p < 0.05). Our study presents the first comprehensive analysis of the influence of environmental/demographic characteristics on global urban microbiome. Our findings indicate that managing air quality and urban greenness is essential for regulating urban microbial diversity and composition. Meanwhile, socio-economic considerations, particularly reducing antibiotic usage in regions with lower GDP, are paramount in curbing the spread of antimicrobial resistance in urban environments.

Irisin ameliorates D-galactose-induced skeletal muscle fibrosis via the PI3K/Akt pathway.

Primary sarcopenia is a multicausal skeletal muscle disease associated with muscle strength and mass loss. Skeletal muscle fibrosis is one of the significant pathological manifestations associated with the development of age-related sarcopenia. Irisin, which is cleaved by the extracellular domain of fibronectin type Ⅲ domain-containing protein 5 (FNDC5), has previously been reported to exert antifibrotic effects on the heart, liver, and pancreas, but whether it can rescue skeletal muscle fibrosis remains unknown. In this study, we examined the effects of irisin on D-galactose (D-gal)-induced skeletal muscle fibroblasts. We found that D-gal-induced senescence, fibrosis, and redox imbalance were inhibited by irisin treatment. Mechanistically, irisin or FNDC5 overexpression attenuated D-gal-induced senescence, redox imbalance, and fibrosis by regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Overall, irisin might be a promising therapeutic candidate for age-related skeletal muscle fibrosis.

Lysyl oxidase-like 2 inhibitor rescues D-galactose-induced skeletal muscle fibrosis.

Aging-related sarcopenia is currently the most common sarcopenia. The main manifestations are skeletal muscle atrophy, replacement of muscle fibers with fat and fibrous tissue. Excessive fibrosis can impair muscle regeneration and function. Lysyl oxidase-like 2 (LOXL2) has previously been reported to be involved in the development of various tissue fibrosis. Here, we investigated the effects of LOXL2 inhibitor on D-galactose (D-gal)-induced skeletal muscle fibroblast cells and mice. Our molecular and physiological studies show that treatment with LOXL2 inhibitor can alleviate senescence, fibrosis, and increased production of reactive oxygen species in fibroblasts caused by D-gal. These effects are related to the inhibition of the TGF-ß1/p38 MAPK pathway. Furthermore, in vivo, mice treatment with LOXL2 inhibitor reduced D-gal-induced skeletal muscle fibrosis, partially enhanced skeletal muscle mass and strength and reduced redox balance disorder. Taken together, these data indicate the possibility of using LOXL2 inhibitors to prevent aging-related sarcopenia, especially with significant fibrosis.