Vitamin D3 Exerts Beneficial Effects on C2C12 Myotubes through Activation of the Vitamin D Receptor (VDR)/Sirtuins (SIRT)1/3 Axis.

The onset of sarcopenia is associated with a decline in vitamin D receptor (VDR) expression, wherein reduced VDR levels contribute to muscle atrophy, while heightened expression promotes muscle hypertrophy. Like VDR, the age-related decline in protein deacetylase sirtuin (SIRT) expression is linked to the development of sarcopenia and age-related muscle dysfunction. This study aimed to investigate whether the VDR agonist 1,25-dihydroxyvitamin D3 (1,25VD3) exerts beneficial effects on muscles through interactions with sirtuins and, if so, the underlying molecular mechanisms. Treatment of 1,25VD3 in differentiating C2C12 myotubes substantially elevated VDR, SIRT1, and SIRT3 expression, enhancing their differentiation. Furthermore, 1,25VD3 significantly enhanced the expression of key myogenic markers, including myosin heavy chain (MyHC) proteins, MyoD, and MyoG, and increased the phosphorylation of AMPK and AKT. Conversely, VDR knockdown resulted in myotube atrophy and reduced SIRT1 and SIRT3 levels. In a muscle-wasting model triggered by IFN-γ/TNF-α in C2C12 myotubes, diminished VDR, SIRT1, and SIRT3 levels led to skeletal muscle atrophy and apoptosis. 1,25VD3 downregulated the increased expression of muscle atrophy-associated proteins, including FoxO3a, MAFbx, and MuRF1 in an IFN-γ/TNF-α induced atrophy model. Importantly, IFN-γ/TNF-α significantly reduced the mtDNA copy number in the C2C12 myotube, whereas the presence of 1,25VD3 effectively prevented this decrease. These results support that 1,25VD3 could serve as a potential preventive or therapeutic agent against age-related muscle atrophy by enhancing the VDR/SIRT1/SIRT3 axis.

Effects of aging-induced obesity on the transcriptional expression of adipogenesis and thermogenic activity in the gonadal white adipose, brown adipose, and skeletal muscle tissues.

PURPOSE: Aging is closely associated with chronic metabolic diseases, such as obesity, which lead to increased adiposity, skeletal muscle wasting, and imbalanced cellular energy metabolism. However, transcriptional profiles representing energy imbalances in aging-induced obesity are not fully understood. Thus, this study aimed to investigate the candidate genes predominantly regulated in aging-related obesity in spontaneously aged mice. METHODS: Male C57BL/6J mice were divided into three age groups according to age: 2- (young), 12- (middle-aged), and 24- (old) months. Body weight and body composition parameters were measured in all mice. Gonadal white adipose tissue (gWAT), brown adipose tissue (BAT), and skeletal muscle (SM) were dissected and weighed. The target tissues were assessed using biochemical and histological assays. RESULTS: Aging-induced obesity increased adipose mass and decreased SM weight through processes of adipocyte hypertrophy; however, recruitment of modulating adipogenesis-inducing transcription factors did not occur. Among adipokines, leptin level was greatly increased in the gWAT during aging. Interestingly, the ß2-adrenergic receptor had a higher affinity than the ß3-adrenergic receptor in aging-induced obesity. For the thermogenic regulation through ß-adrenergic receptors (ß-ARs), a declined uncoupling protein-1 (UCP-1) in the BAT was relevant to aging-induced obesity. CONCLUSION: Aging-induced obesity increases leptin levels in adipocytes and decreases UCP-1 in BAT through ß-ARs, according to transcriptional gene profiling. WAT browning increases energy expenditure due to exercise training adaptations. Further research is needed to discover more effective methods, such as exercise, against aging-induced obesity.