Skeletal muscle-specific calpastatin overexpression mitigates muscle weakness in aging and extends life span.
Skeletal muscle-specific calpastatin overexpression mitigates muscle weakness in aging and extends life span.
复制标题
骨骼肌特异性钙蛋白酶抑制素过度表达可减轻衰老过程中的肌肉无力并延长寿命。
DOI：
10.1152/japplphysiol.00883.2020
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Supinski,GeraldS
中科院分区：
文献类型：
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作者：
Schroder,ElizabethA;Wang,Lin;Wen,Yuan;Callahan,LeighAnnP;Supinski,GeraldS
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因素，但以前的实验方法的局限性未能完全检验这一问题。我们假设，仅在骨骼肌中过度表达Calastatin(CalpOX)的小鼠将显示衰老肌肉表型的改善。CalpOX是一种钙蛋白酶的内源性抑制剂。我们评估了四组小鼠(月龄)：1)年轻野生型(WT；5.71±0.43)，2)年轻CalpOX(5.6±0.5)，3)老年WT(25.81±0.56)，4)老年CalpOX(25.91±0.60)横隔肌和四肢肌(指长伸肌，EDL)的力频率关系。衰老显著降低老年WT小鼠的横隔膜和EDL峰值力量，并使老年WT横隔膜和EDL小鼠疲劳过程中的力-时间积分分别减少48%和23%。相反，我们发现CalpOX小鼠在老年小鼠的横隔膜和EDL峰值力量显著增加，与在年轻小鼠中观察到的相似。衰老对疲劳过程中的力-时间积分的影响在老年CalpOX动物的横隔膜和EDL中被取消。令人惊讶的是，我们发现CalpOX对寿命有显著影响，将WT小鼠的中位生存期从20.55mo提高到CalpOX小鼠的24mo(P=0.0006)。
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): 1) young wild type (WT; 5.71±0.43), 2) young CalpOX (5.6±0.5), 3) old WT (25.81±0.56), and 4) 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 (P= 0.0006).