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BACKGROUND

Age-related sarcopenia, characterized by reduced skeletal muscle mass and function, significantly affects the health of the elderly individuals. Oxidative stress plays a crucial role in the development of sarcopenia. Tripartite motif containing 16 (TRIM16) is implicated in orchestrating antioxidant responses to mitigate oxidative stress, yet its regulatory role in skeletal muscle remains unclear. This study aims to elucidate the impact of TRIM16 on enhancing antioxidant response through SIRT-1, consequently mitigating age-related oxidative stress, and ameliorating muscle atrophy.

METHODS

Aged mouse models were established utilizing male mice at 18 months with D-galactose (D-gal, 200 mg/kg) intervention and at 24 months with natural aging, while 3-month-old young mice served as controls. Muscle cell senescence was induced in C2C12 myoblasts using 30 g/L D-gal. TRIM16 was overexpressed in the skeletal muscle of aged mice and silenced/overexpressed in C2C12 myoblasts. The effects of TRIM16 on skeletal muscle mass, grip strength, morphological changes, myotube formation, myogenic differentiation, and muscle atrophy indicators were evaluated. Reactive oxygen species (ROS) levels and oxidative stress-related parameters were measured. The SIRT-1 inhibitor EX-527 was employed to elucidate the protective role of TRIM16 mediated through SIRT-1.

RESULTS

Aged mice displayed significant reductions in lean mass (-11.58%; -14.47% vs. young, P < 0.05), hindlimb lean mass (-17.38%; -15.95% vs. young, P < 0.05), and grip strength (-22.29%; -31.45% vs. young, P < 0.01). Skeletal muscle fibre cross-sectional area (CSA) decreased (-29.30%; -24.12% vs. young, P < 0.05). TRIM16 expression significantly decreased in aging skeletal muscle (-56.82%; -66.27% vs. young, P < 0.001) and senescent muscle cells (-46.53% vs. control, P < 0.001). ROS levels increased (+69.83% vs. control, P < 0.001), and myotube formation decreased in senescent muscle cells (-56.68% vs. control, P < 0.001). Expression of myogenic differentiation and antioxidant indicators decreased, while muscle atrophy markers increased in vivo and in vitro (all P < 0.05). Silencing TRIM16 in myoblasts induced oxidative stress and myotube atrophy, while TRIM16 overexpression partially mitigated aging effects on skeletal muscle. TRIM16 activation enhanced SIRT-1 expression (+75.38% vs. control, P < 0.001). SIRT-1 inhibitor EX-527 (100 μM) suppressed TRIM16's antioxidant response and mitigating muscle atrophy, offsetting the protective effect of TRIM16 on senescent muscle cells.

CONCLUSIONS

This study elucidates TRIM16's role in mitigating oxidative stress and ameliorating muscle atrophy through the activation of SIRT-1-dependent antioxidant effects. TRIM16 emerges as a potential therapeutic target for age-related sarcopenia.

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

背景

与年龄相关的肌肉减少症，其特征是骨骼肌质量和功能下降，对老年人的健康有显著影响。氧化应激在肌肉减少症的发展中起关键作用。含三联基序蛋白16（TRIM16）参与协调抗氧化反应以减轻氧化应激，但其在骨骼肌中的调节作用尚不清楚。本研究旨在阐明TRIM16通过沉默信息调节因子1（SIRT-1）增强抗氧化反应、减轻与年龄相关的氧化应激以及改善肌肉萎缩的影响。

方法

利用18个月大的雄性小鼠经D-半乳糖（D-gal，200mg/kg）干预建立衰老小鼠模型，以及24个月自然衰老的雄性小鼠，3个月大的年轻小鼠作为对照。用30g/L D-半乳糖诱导C2C12成肌细胞发生肌肉细胞衰老。在衰老小鼠的骨骼肌中过表达TRIM16，并在C2C12成肌细胞中沉默/过表达TRIM16。评估TRIM16对骨骼肌质量、握力、形态变化、肌管形成、成肌分化和肌肉萎缩指标的影响。测量活性氧（ROS）水平和氧化应激相关参数。使用SIRT-1抑制剂EX-527来阐明TRIM16通过SIRT-1介导的保护作用。

结果

衰老小鼠的瘦体重（-11.58%；与年轻小鼠相比为-14.47%，P<0.05）、后肢瘦体重（-17.38%；与年轻小鼠相比为-15.95%，P<0.05）和握力（-22.29%；与年轻小鼠相比为-31.45%，P<0.01）显著降低。骨骼肌纤维横截面积（CSA）减小（-29.30%；与年轻小鼠相比为-24.12%，P<0.05）。TRIM16在衰老骨骼肌中的表达显著降低（-56.82%；与年轻小鼠相比为-66.27%，P<0.001），在衰老肌肉细胞中的表达也显著降低（与对照相比为-46.53%，P<0.001）。衰老肌肉细胞中的ROS水平升高（与对照相比+69.83%，P<0.001），肌管形成减少（与对照相比-56.68%；P<0.001）。体内和体外成肌分化和抗氧化指标的表达降低，而肌肉萎缩标志物增加（均P<0.05）。在成肌细胞中沉默TRIM16会诱导氧化应激和肌管萎缩，而TRIM16过表达可部分减轻衰老对骨骼肌的影响。TRIM16激活可增强SIRT-1表达（与对照相比+75.38%，P<于0.001）。SIRT-1抑制剂EX-527（100μM）抑制TRIM16的抗氧化反应并减轻肌肉萎缩，抵消了TRIM16对衰老肌肉细胞的保护作用。