Counteracting sarcopenia: the role of IGF-1 isoforms

Among growth factors, the insulin-like growth factor-1 (IGF-1) have been implicated in the control of skeletal muscle growth, differentiation, and regeneration and has emerged as a growth factor with a remarkably wide range of actions and a tremendous potential as a therapeutic factor in attenuating the atrophy and frailty associated with muscle ageing and diseases [3, 4]. In the adult mammals, IGF-1 is principally synthesized in the liver, acting as a systemic growth factor; however, it is also produced in extrahepatic tissues, including skeletal muscle, where it mainly plays an autocrine/paracrine role. The IGF-1 protein is produced by different prepro-peptides, whereas two different promoters and differential splicing of the IGF-1 gene create several IGF-1 isoforms, which differ in the N-terminal signalpeptide (Class 1 or 2) and the C-terminal Extension peptide (E-peptide Ea or Eb) [3]. Given the conflicting and still unclear data on effects of different IGF-1 isoforms, a recent study investigated whether the muscle overexpression of either propeptides IGF-1Ea or IGF-1Eb isoform impacts sarcopenia and through which mechanisms each isoform acts [5]. Muscle restricted over-expression of both IGF-1Ea and IGF-1Eb isoforms did not induce any significant change in the circulating IGF-1 levels in young mice compared to age-matched wild type animals. Interestingly, consistent with the physiological decline of IGF-1 plasma levels during aging, a strong reduction of IGF-1 levels was observed in old wild type mice [5]. On the contrary, aged transgenic animals showed unchanged levels of circulating IGF-1 compared to young counterparts, thus resulting higher compared to old wild type mice. It is possible to speculate that IGF-1 isoforms, locally expressed, exert an indirect systemic effect, contributing to the maintenance of circulating IGF-1 levels during postnatal life. Indeed, skeletal muscle has recently been identified as an endocrine organ, able to produce and release cytokines and other peptides, such as the myokines, that act in paracrine, autocrine, or endocrine manner [6]. In this context, muscle can be also a source