IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1

Abstract

Localized synthesis of insulin-like growth factors (IGFs) has been broadly implicated in skeletal muscle growth, hypertrophy and regeneration. Virally delivered IGF-1 genes induce local skeletal muscle hypertrophy and attenuate age-related skeletal muscle atrophy, restoring and improving muscle mass and strength in mice. Here we show that the molecular pathways underlying the hypertrophic action of IGF-1 in skeletal muscle are similar to those responsible for cardiac hypertrophy. Transfected IGF-1 gene expression in postmitotic skeletal myocytes activates calcineurin-mediated calcium signalling by inducing calcineurin transcripts and nuclear localization of calcineurin protein. Expression of activated calcineurin mimics the effects of IGF-1, whereas expression of a dominant-negative calcineurin mutant or addition of cyclosporin, a calcineurin inhibitor, represses myocyte differentiation and hypertrophy. Either IGF-1 or activated calcineurin induces expression of the transcription factor GATA-2, which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of the transcription factor NF-ATc1. Thus, IGF-1 induces calcineurin-mediated signalling and activation of GATA-2, a marker of skeletal muscle hypertrophy, which cooperates with selected NF-ATc isoforms to activate gene expression programs.

The adaptation of soleus and edl in a rat model of distraction osteogenesis: IGF‐1 and fibrosis

“…In particular IGF-1 is a growth stimulating agent for muscle cells in vitro [11,25,28,35] and in vivo [3], although the in vivo role of IGF-1 in stimulating muscle growth in adult animals is less clear and may rely in part on the presence of growth hormone [21]. Recent evidence also suggests that muscle growth in response to stretch is associated with the expression of an alternatively spliced form of IGF-1 [15,39].…”

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

“…In cardiac muscle, calcineurin signalling is necessary for cardiomyocyte maturation, heart chamber formation and cardiac hypertrophy (Schulz and Yutzey, 2004). In skeletal muscle, calcineurin appears to be needed in a number of key developmental processes, namely enhanced muscle cell differentiation, and in the fibre type context, conversion to slow (oxidative) muscle phenotype (Musarò et al, 1999;Semsarian et al, 1999;Bigard et al, 2000;Delling et al, 2000). It has been reported that activated calcineurin mediates the hypertrophic effect of IGF-1 (Musarò et al, 1999;Semsarian et al, 1999).…”

“…In skeletal muscle, calcineurin appears to be needed in a number of key developmental processes, namely enhanced muscle cell differentiation, and in the fibre type context, conversion to slow (oxidative) muscle phenotype (Musarò et al, 1999;Semsarian et al, 1999;Bigard et al, 2000;Delling et al, 2000). It has been reported that activated calcineurin mediates the hypertrophic effect of IGF-1 (Musarò et al, 1999;Semsarian et al, 1999). However, there is compelling evidence, including transgenic and knock-out data, to show that calcineurin has no effect on muscle hypertrophy but that the hypertrophic effect of IGF-1 is mediated by the PI3K pathway as detailed earlier (Naya et al, 2000;Bodine et al, 2001b;Rommel et al, 2001;Pallafacchina et al, 2002).…”

“…For instance, NFATc2 is activated only in new myotubes and plays a crucial role via IL-4 in mediating myoblast fusion (Horsley et al, 2003). Dephosphorylation of NFATs unmasks their nuclear localisation signal, resulting in nuclear translocation, where they bind to NFAT-binding sites on their own or as cooperative complexes with other factors, such as calcineurin, AP1, MEF2 and GATA2/4, to activate gene transcription (Musarò et al, 1999;Sugiura et al, 2001;Schulz and Yutzey, 2004). Cultured muscle fibres showed NFAT nuclear translocation only when electrically stimulated at a slow muscle pattern, which results in high intracellular calcium (100 to 300 nM) but not at a fast muscle pattern that results in low intracellular calcium (,50 nM) (Liu et al, 2001;Fraysse et al, 2003).…”

“…Factors involved in signalling, muscle metabolism or sarcomeric structure that are associated with the process of muscle hypertrophy could potentially be used as hypertrophic markers. GATA-2 has been recently identified as a potentially useful candidate marker gene of muscle hypertrophy (Musarò et al, 1999;Paul and Rosenthal, 2002). In mammals, the GATA zinc-finger transcription factor family comprises six gene members that can be divided into 2 sub-groups, based on structure and function (LaVoie, 2003).…”