Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models

Abstract

A highly conserved signaling pathway involving insulin-like growth factor 1 (IGF1), and a cascade of intracellular components that mediate its effects, plays a major role in the regulation of skeletal muscle growth. A central component in this cascade is the kinase Akt, also called protein kinase B (PKB), which controls both protein synthesis, via the kinases mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β), and protein degradation, via the transcription factors of the FoxO family. In this paper, we review the composition and function of this pathway in skeletal muscle fibers, focusing on evidence obtained in vivo by transgenic and knockout models and by muscle transient transfection experiments. Although this pathway is essential for muscle growth during development and regeneration, its role in adult muscle response to mechanical load is less clear. A full understanding of the operation of this pathway could help to design molecularly targeted therapeutics aimed at preventing muscle wasting, which occurs in a variety of pathologic contexts and in the course of aging.

Figure 1

The insulin-like growth factor 1 (IGF1)-Akt pathway controls muscle growth via mammalian target of rapamycin (mTOR) and FoxO. The internal feedback loops that control the IGF1-Akt pathway are indicated in red. The dotted line indicates that the effect of Akt on mTOR is indirect, being mediated by the tuberous sclerosis complex (TSC) proteins 1 and 2 and by Rheb (Ras homolog enriched in brain). See text for details.

Figure 2

The insulin-like growth factor 1 (IGF1)-Akt pathway controls muscle growth also via glycogen synthase kinase β (GSK3β). GSK3β inhibits protein synthesis via eukaryotic initiation factor 2B (eIF2B) and actin filament formation via nebulin and neuronal Wiscott-Aldrich syndrome protein (N-WASP). See text for details.

Figure 3

Multiple factors and pathways affect insulin-like growth factor 1 (IGF1)-Akt signaling. Various factors and pathways affecting the IGF1-Akt pathway are highlighted in red. See text for details.

Figure 4

Myofiber hypertrophy or atrophy induced by transfection of skeletal muscle with mutants of Akt or FoxO. (A) Regenerating rat soleus muscle transfected with plasmid coding for constitutively active Akt1 linked to a hemagglutinin (HA) epitope. Muscle examined 7 days after transfection; section stained for the HA tag. Note the striking hypertrophy of labeled myofibers compared with untransfected neighbouring fibers. Modified from [69]. (B,C) Adult mouse tibialis anterior muscle transfected by electroporation with plasmid coding for constitutively active Ha-tagged FoxO3. Muscle examined 14 days after transfection; section stained for the HA tag. Note the striking atrophy of labeled myofibers compared with untransfected neighboring fibers. A phase-contrast image of the same field is shown in the right panel. Modified from [91].