Counteracting muscle wasting in aging and neuromuscular diseases: the critical role of IGF-1

Abstract

Most muscle pathologies are characterized by the progressive loss of muscle tissue due to chronic degeneration combined with the inability of regeneration machinery to replace the damaged muscle. These pathological changes, known as muscle wasting, can be attributed to the activation of several proteolytic systems, such as calpain, ubiquitin-proteasome and caspases, and to the alteration in muscle growth factors. Among them, insulin-like growth factor-1 (IGF-1) has been implicated in the control of skeletal muscle growth, differentiation, survival, and regeneration and has been considered a promising therapeutic agent in staving off the advance of muscle weakness. Here we review the molecular basis of muscle wasting associated with diseases, such as sarcopenia, muscular dystrophy and Amyotrophic Lateral Sclerosis, and discuss the potential therapeutic role of local IGF-1 isoforms in muscle aging and diseases.

Keywords: ALS; Aging; IGF-1; muscle wasting; muscular dystrophy; neuromuscular diseases.

Figure 1.. Schematic representation of rodent IGF-1 gene.

The rodent IGF-1 gene contains six exons (colored boxes), separated by five introns (black lines). Both exons 1 and 2 contain multiple transcription start sites (horizontal arrows). Translation initiation codons (AUG) are located at exons 1, 2 and 3 (vertical arrows). Exons 1, 2 and 3 code for the signal peptide of precursor IGF-1 (red boxes). Exons 5 and 6 each encode distinct portions of the E-peptides (green boxes).

Figure 2.. Model of stem cell-mediated muscle regeneration.

(modified from ref. 18). Muscle injury involves the activation of satellite cells and the recruitment of circulating stem cells, which when penetrating the muscle compartment receive myogenic signals and may contribute to muscle regeneration and repair. This process is enhanced by mIGF-1 expression. By modulating the inflammatory response and reducing fibrosis, supplemental mIGF-1 creates a qualitatively different environment for sustaining more efficient muscle regeneration and repair.