Wang Tiantian, Chen Sihan, Zhou Dong, Hong Zhen
Department of Neurology, Institute of Neurology and Disease, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
West China School of Nursing, Sichuan University, Chengdu, Sichuan, China.
Metabolism. 2025 Apr;165:156148. doi: 10.1016/j.metabol.2025.156148. Epub 2025 Jan 30.
Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The underlying mechanisms contributing to these pathological changes remain poorly understood. We propose that chronic inflammation-mediated networks and metabolic defects that exacerbate muscle dysfunction are critical factors in sarcopenia and related diseases. Consequently, utilizing specialized pro-resolving mediators (SPMs) that function through specific G-protein coupled receptors (GPCRs) may offer effective therapeutic options for these disorders. However, challenges such as a limited understanding of SPM/receptor signaling pathways, rapid inactivation of SPMs, and the complexities of SPM synthesis impede their practical application. In this context, stable small-molecule SPM mimetics and receptor agonists present promising alternatives. Moreover, the aged adipose-skeletal axis may contribute to this process. Activating non-SPM GPCRs on adipocytes, immune cells, and muscle cells under conditions of systemic, chronic, low-grade inflammation (SCLGI) could help alleviate inflammation and metabolic dysfunction. Recent preclinical studies indicate that both SPM GPCRs and non-SPM GPCRs can mitigate symptoms of aging-related diseases such as obesity and diabetes, which are driven by chronic inflammation and metabolic disturbances. These findings suggest that targeting these receptors could provide a novel strategy for addressing various chronic inflammatory conditions, including sarcopenia.
肌肉减少症的定义是肌肉力量和质量均下降。肌肉减少症可能是衰老过程中不可避免的一部分，但也可能因合并症和代谢紊乱而加速。导致这些病理变化的潜在机制仍知之甚少。我们认为，慢性炎症介导的网络和加剧肌肉功能障碍的代谢缺陷是肌肉减少症及相关疾病的关键因素。因此，利用通过特定G蛋白偶联受体（GPCRs）发挥作用的特殊促消退介质（SPMs）可能为这些疾病提供有效的治疗选择。然而，诸如对SPM/受体信号通路了解有限、SPMs快速失活以及SPM合成的复杂性等挑战阻碍了它们的实际应用。在这种情况下，稳定的小分子SPM模拟物和受体激动剂是有前景的替代方案。此外，衰老的脂肪-骨骼轴可能促成这一过程。在全身慢性低度炎症（SCLGI）条件下激活脂肪细胞、免疫细胞和肌肉细胞上的非SPM GPCRs有助于减轻炎症和代谢功能障碍。最近的临床前研究表明，SPM GPCRs和非SPM GPCRs都可以减轻由慢性炎症和代谢紊乱驱动的肥胖和糖尿病等衰老相关疾病的症状。这些发现表明，靶向这些受体可能为解决包括肌肉减少症在内的各种慢性炎症性疾病提供一种新策略。
