Abstract
The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin‐like growth factor‐1 (IGF‐1) has been implicated in many anabolic pathways in skeletal muscle. IGF‐1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF‐1Ea and IGF‐1Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF‐1Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF‐1Ea or IGF‐1Eb transgenes was protective against age‐related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase PGC1‐α expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF‐1Ea and MLC/IGF‐1Eb mice during aging. These data suggest that IGF‐1 is a promising therapeutic agent in staving off advancing muscle weakness.
Highlights
The progressive age‐related decline in skeletal muscle mass and strength, responsible for impaired mobility and disability in el‐ derly, is referred as sarcopenia, and it is the result of multiple molecular and cellular changes
Given the conflicting and still unclear data on effects of different insulin‐like growth factor‐1 (IGF‐1) isoforms, we propose to study the function of the full‐length Class1_IGF‐1 Ea and Class1_IGF‐1Eb isoforms in skeletal muscle, with the purpose to investigate whether the overexpression of either propeptides IGF‐1Ea or IGF‐1Eb isoform impacts muscle aging and through which mechanisms each isoform acts
We analyzed the effects of overexpression of full‐ length Class 1 IGF‐1Ea and Class 1 IGF‐1Eb isoforms on muscle growth and their ability to counteract sarcopenia
Summary
The progressive age‐related decline in skeletal muscle mass and strength, responsible for impaired mobility and disability in el‐ derly, is referred as sarcopenia, and it is the result of multiple molecular and cellular changes. The evaluation of visceral organs weight and the morphologic and molecular analyses of the cardiac tissue revealed that skeletal muscle‐specific expression of IGF‐1 isoforms caused no significant changes in transgenic mice compared to wild type littermates (data not shown). The increase in ROS production in the muscle of aged IGF‐1Ea mice was compensated with the modulation of relevant en‐ ergy sensors, such as AMPK (Figure 4d), and of markers with anti‐ oxidant activity, namely PGC1‐α and Nrf‐2 (Figure 4e,f) Consistent with these data, we found that the levels of mRNAs that en‐ code the rate‐limiting enzyme for glutathione biosynthesis (glutamyl cysteine ligase modulator, GCLM) and catalase, a ROS scavenging enzyme, were significantly up‐regulated in old IGF‐1Ea, compared with wild‐type and IGF‐1Eb littermates (Figure 4g,h). Histological analysis, by α‐bungarotoxin staining on the longitudinal sections of quadriceps
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