Jang Hye Rim, Park Shi-Young, Lee Yeonmi, Lee Dongjin, Lee Jongjun, Cho Yoonil, Choi Cheol Soo, Lee Hui-Young
Laboratory of Mitochondria and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
Department of Health Sciences and Technology. GAIHST, Gachon University, Incheon, Republic of Korea.
J Cachexia Sarcopenia Muscle. 2025 Aug;16(4):e70007. doi: 10.1002/jcsm.70007.
Maintaining skeletal muscle mass and strength is crucial to prevent sarcopenia during healthy ageing. Ankyrin repeat and suppressor of cytokine signalling box protein 2 (Asb2), an E3 ligase, has been implicated in regulating muscle mass; however, its roles on muscle strength remain unclear, with mixed findings from previous studies. Overexpression of Asb2 decreases muscle mass, whereas its knockdown delays myoblast differentiation and reduces contractile proteins. Given these contradictory findings, we aimed to clarify the role of Asb2 in muscle mass and strength using a skeletal muscle-specific Asb2 knockout (Asb2 MKO) mouse model. Additionally, we investigate the long-term effects of Asb2 on aged muscle, underlying mechanisms on muscle regulation and metabolic effects of Asb2 MKO mice to better understand its role in muscle function and age-related metabolic diseases.
Asb2 MKO mice were generated using Acta1-Cre recombinase. Body composition was quantified in male and female mice up to 18 months of age. Muscle strength, energy expenditure and glucose metabolism were evaluated using the grip strength test, mitochondrial oxygen consumption measurement, indirect calorimetry and glucose/insulin tolerance tests. Transcriptomic analyses and siRNA studies were performed to elucidate the mechanisms underlying the Asb2 deletion.
The MKO mice were born healthy and exhibited selective Asb2 deletion in the skeletal muscle, leaving the cardiac muscle unaffected. This deletion led to an increase in the mass of various skeletal muscles (9%-23%, p < 0.05) and improved grip strength (~10%, p < 0.05), both of which were sustained throughout the ageing process. The MKO mice also revealed enhanced mitochondrial function, energy expenditure and whole-body insulin sensitivity. Transcriptomic data supported the muscle phenotype observed in the MKO mice. Notably, desmin, a protein critical for structural integrity and mitochondrial function, was identified as a target protein of the ASB2 E3 ligase.
Skeletal muscle-specific deletion of Asb2 led to increased muscle mass and strength, potentially through preservation of desmin levels. These findings suggest that targeting Asb2 may enhance muscle growth and prevent age-related muscle decline, with potential benefits for metabolic health, particularly by improving mitochondrial function and insulin sensitivity.
在健康衰老过程中，维持骨骼肌质量和力量对于预防肌肉减少症至关重要。锚蛋白重复序列和细胞因子信号抑制盒蛋白2（Asb2）作为一种E3连接酶，已被证实参与调节肌肉质量；然而，其对肌肉力量的作用仍不明确，先前研究结果不一。Asb2的过表达会降低肌肉质量，而敲低它则会延迟成肌细胞分化并减少收缩蛋白。鉴于这些相互矛盾的发现，我们旨在使用骨骼肌特异性Asb2基因敲除（Asb2 MKO）小鼠模型来阐明Asb2在肌肉质量和力量方面的作用。此外，我们研究了Asb2对衰老肌肉的长期影响、肌肉调节的潜在机制以及Asb2 MKO小鼠的代谢效应，以更好地理解其在肌肉功能和与年龄相关的代谢疾病中的作用。
使用Acta1-Cre重组酶构建Asb2 MKO小鼠。对18个月龄以内的雄性和雌性小鼠进行身体成分定量分析。通过握力测试、线粒体氧消耗测量、间接量热法以及葡萄糖/胰岛素耐量试验来评估肌肉力量、能量消耗和葡萄糖代谢。进行转录组分析和siRNA研究以阐明Asb2缺失的潜在机制。
MKO小鼠出生时健康，骨骼肌中出现选择性Asb2缺失，而心肌未受影响。这种缺失导致各种骨骼肌质量增加（9%-23%，p<0.05），握力增强（约10%，p<0.05），且在整个衰老过程中均保持。MKO小鼠还表现出线粒体功能、能量消耗和全身胰岛素敏感性增强。转录组数据支持在MKO小鼠中观察到的肌肉表型。值得注意的是，结蛋白是一种对结构完整性和线粒体功能至关重要的蛋白质，被确定为ASB2 E3连接酶的靶蛋白。
骨骼肌特异性缺失Asb2可能通过维持结蛋白水平导致肌肉质量和力量增加。这些发现表明，靶向Asb2可能促进肌肉生长并预防与年龄相关的肌肉衰退，对代谢健康具有潜在益处，特别是通过改善线粒体功能和胰岛素敏感性。
