Pulmonary Division, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky.
Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky.
J Appl Physiol (1985). 2021 Aug 1;131(2):630-642. doi: 10.1152/japplphysiol.00883.2020. Epub 2021 Jul 1.
Calpain activation has been postulated as a potential contributor to the loss of muscle mass and function associated with both aging and disease, but limitations of previous experimental approaches have failed to completely examine this issue. We hypothesized that mice overexpressing calpastatin (CalpOX), an endogenous inhibitor of calpain, solely in skeletal muscle would show an amelioration of the aging muscle phenotype. We assessed four groups of mice (age in months): ) young wild type (WT; 5.71 ± 0.43), ) young CalpOX (5.6 ± 0.5), ) old WT (25.81 ± 0.56), and ) old CalpOX (25.91 ± 0.60) for diaphragm and limb muscle (extensor digitorum longus, EDL) force frequency relations. Aging significantly reduced diaphragm and EDL peak force in old WT mice, and decreased the force-time integral during a fatiguing protocol by 48% and 23% in aged WT diaphragm and EDL, respectively. In contrast, we found that CalpOX mice had significantly increased diaphragm and EDL peak force in old mice, similar to that observed in young mice. The impact of aging on the force-time integral during a fatiguing protocol was abolished in the diaphragm and EDL of old CalpOX animals. Surprisingly, we found that CalpOX had a significant impact on longevity, increasing median survival from 20.55 mo in WT mice to 24 mo in CalpOX mice ( = 0.0006). This is the first study to investigate the role of calpastatin overexpression on skeletal muscle specific force in aging rodents. Muscle-specific overexpression of calpastatin, the endogenous calpain inhibitor, prevented aging-induced reductions in both EDL and diaphragm specific force and, remarkably, increased life span. These data suggest that diaphragm dysfunction in aging may be a major factor in determining longevity. Targeting the calpain/calpastatin pathway may elucidate novel therapies to combat skeletal muscle weakness in aging.
钙蛋白酶的激活被认为是与衰老和疾病相关的肌肉质量和功能丧失的潜在原因，但先前实验方法的局限性未能完全解决这个问题。我们假设，仅在骨骼肌中过表达钙蛋白酶抑制剂钙蛋白酶抑制蛋白（CalpOX）的小鼠将改善衰老肌肉表型。我们评估了四组小鼠（月龄）：）年轻野生型（WT；5.71±0.43），）年轻 CalpOX（5.6±0.5），）老年 WT（25.81±0.56）和）老年 CalpOX（25.91±0.60）的膈肌和肢体肌肉（伸趾长肌，EDL）力频率关系。衰老显著降低了老年 WT 小鼠的膈肌和 EDL 峰值力，并使老年 WT 膈肌和 EDL 疲劳协议中的力时间积分分别降低了 48%和 23%。相比之下，我们发现 CalpOX 小鼠在老年小鼠中具有显著增加的膈肌和 EDL 峰值力，类似于年轻小鼠中的观察结果。在老年 CalpOX 动物的膈肌和 EDL 中，衰老对疲劳协议期间力时间积分的影响被消除。令人惊讶的是，我们发现 CalpOX 对寿命有显著影响，将 WT 小鼠的中位寿命从 20.55 个月增加到 CalpOX 小鼠的 24 个月（=0.0006）。这是第一项研究钙蛋白酶抑制蛋白过表达对衰老啮齿动物骨骼肌特定力的作用。钙蛋白酶的肌肉特异性过表达，即内源性钙蛋白酶抑制剂，可防止 EDL 和膈肌特定力因衰老而降低，并且显著增加了寿命。这些数据表明，衰老过程中膈肌功能障碍可能是决定寿命的一个重要因素。靶向钙蛋白酶/钙蛋白酶抑制蛋白途径可能阐明治疗衰老相关骨骼肌无力的新疗法。
