Gonzalez Estela, Messi María Laura, Zheng Zhenlin, Delbono Osvaldo
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
J Physiol. 2003 Nov 1;552(Pt 3):833-44. doi: 10.1113/jphysiol.2003.048165. Epub 2003 Aug 22.
In the present work we test the hypothesis that sustained transgenic overexpression of insulin-like growth factor-1 (IGF-1) in skeletal muscle prevents age-related decreases in myoplasmic Ca2+ concentration and consequently in specific force in single intact fibres from the flexor digitorum brevis (FDB) muscle from the mouse. Measurements of IGF-1 concentration in FDB muscle showed higher levels in transgenic than in wild-type mice at all ages. The specific tetanic force decreased significantly in single muscle fibres from old (286 +/- 22 kPa) compared to young wild-type (455 +/- 28 kPa), young transgenic (423 +/- 43 kPa), and old transgenic mice (386 +/- 15 kPa) (P < 0.05). These results are consistent with measurements in whole FDB muscles. The peak Ca2+ concentration values in response to prolonged stimulation were: 1.47 +/- 0.15, 1.70 +/- 0.29, 0.97 +/- 0.13 and 1.7 +/- 0.22 microM, in fibres from young wild-type, young transgenic, old wild-type and old transgenic mice, respectively. The effects of caffeine on FDB fibres support the conclusion that the age-related decline in peak myoplasmic Ca2+ and specific force is not explained by sarcoplasmic reticulum Ca2+ depletion. Immunohistochemistry in muscle cross-sections was performed to determine whether age and/or IGF-1 overexpression induce changes in fibre type composition. The relative percentages of type IIa, IIx and I myosin heavy chain (MHC) isoforms did not change significantly with age or genotype. Therefore, IGF-1 prevents age-related decline in peak intracellular Ca2+ and specific force in a muscle that does not exhibit changes in fibre type composition with senescence.
在本研究中，我们验证了以下假设：骨骼肌中胰岛素样生长因子-1（IGF-1）的持续转基因过表达可防止小鼠屈趾短肌（FDB）单根完整肌纤维中肌浆Ca2+浓度以及由此导致的比肌力随年龄增长而下降。FDB肌肉中IGF-1浓度的测量结果显示，在所有年龄段，转基因小鼠中的IGF-1水平均高于野生型小鼠。与年轻野生型（455±28 kPa）、年轻转基因（423±43 kPa）和老年转基因小鼠（386±15 kPa）相比，老年小鼠单根肌纤维中的强直比肌力显著下降（P<0.05）。这些结果与整个FDB肌肉的测量结果一致。在长时间刺激下，年轻野生型、年轻转基因、老年野生型和老年转基因小鼠纤维中Ca2+浓度峰值分别为：1.47±0.15、1.70±0.29、0.97±0.13和1.7±0.22 μM。咖啡因对FDB纤维的作用支持了以下结论：肌浆Ca2+峰值和比肌力随年龄增长而下降并非由肌浆网Ca2+耗竭所致。对肌肉横切面进行免疫组织化学分析，以确定年龄和/或IGF-1过表达是否会引起纤维类型组成的变化。IIa型、IIx型和I型肌球蛋白重链（MHC）亚型的相对百分比并未随年龄或基因型发生显著变化。因此，在衰老过程中纤维类型组成未发生变化的肌肉中，IGF-1可防止细胞内Ca2+峰值和比肌力随年龄增长而下降。
