Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective degeneration of motor neurons, atrophy, and paralysis of skeletal muscle. Although a significant proportion of familial ALS results from a toxic gain of function associated with dominant SOD1 mutations, the etiology of the disease and its specific cellular origins have remained difficult to define. Here, we show that muscle-restricted expression of a localized insulin-like growth factor (Igf) -1 isoform maintained muscle integrity and enhanced satellite cell activity in SOD1G93A transgenic mice, inducing calcineurin-mediated regenerative pathways. Muscle-specific expression of local Igf-1 (mIgf-1) isoform also stabilized neuromuscular junctions, reduced inflammation in the spinal cord, and enhanced motor neuronal survival in SOD1G93A mice, delaying the onset and progression of the disease. These studies establish skeletal muscle as a primary target for the dominant action of inherited SOD1 mutation and suggest that muscle fibers provide appropriate factors, such as mIgf-1, for neuron survival.

Muscle regeneration following injury is characterized by myonecrosis accompanied by local inflammation, activation of satellite cells, and repair of injured fibers. The resolution of the inflammatory response is necessary to proceed toward muscle repair, since persistence of inflammation often renders the damaged muscle incapable of sustaining efficient muscle regeneration. Here, we show that local expression of a muscle-restricted insulin-like growth factor (IGF)-1 (mIGF-1) transgene accelerates the regenerative process of injured skeletal muscle, modulating the inflammatory response, and limiting fibrosis. At the molecular level, mIGF-1 expression significantly down-regulated proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, and modulated the expression of CC chemokines involved in the recruitment of monocytes/macrophages. Analysis of the underlying molecular mechanisms revealed that mIGF-1 expression modulated key players of inflammatory response, such as macrophage migration inhibitory factor (MIF), high mobility group protein-1 (HMGB1), and transcription NF-kappaB. The rapid restoration of injured mIGF-1 transgenic muscle was also associated with connective tissue remodeling and a rapid recovery of functional properties. By modulating the inflammatory response and reducing fibrosis, supplemental mIGF-1 creates a qualitatively different environment for sustaining more efficient muscle regeneration and repair.

We investigated the mechanism whereby expression of a transgene encoding a locally acting isoform of insulin-like growth factor 1 (mIGF-1) enhances repair of skeletal muscle damage. Increased recruitment of proliferating bone marrow cells to injured MLC͞ mIgf-1 transgenic muscles was accompanied by elevated bone marrow stem cell production in response to distal trauma. Regenerating MLC͞mIgf-1 transgenic muscles contained increased cell populations expressing stem cell markers, exhibited accelerated myogenic differentiation, expressed markers of regeneration and readily converted cocultured bone marrow to muscle. These data implicate mIGF-1 as a powerful enhancer of the regeneration response, mediating the recruitment of bone marrow cells to sites of tissue damage and augmenting local repair mechanisms.

The peculiar ability of skeletal muscle tissue to operate adaptive changes during post-natal development and adulthood has been associated with the existence of adult somatic stem cells. Satellite cells, occupying an exclusive niche within the adult muscle tissue, are considered bona fide stem cells with both stem-like properties and myogenic activities. Indeed, satellite cells retain the capability to both maintain the quiescence in uninjured muscles and to be promptly activated in response to growth or regenerative signals, re-engaging the cell cycle. Activated cells can undergo myogenic differentiation or self-renewal moving back to the quiescent state. Satellite cells behavior and their fate decision are finely controlled by mechanisms involving both cell-autonomous and external stimuli. Alterations in these regulatory networks profoundly affect muscle homeostasis and the dynamic response to tissue damage, contributing to the decline of skeletal muscle that occurs under physio-pathologic conditions. Although the clear myogenic activity of satellite cells has been described and their pivotal role in muscle growth and regeneration has been reported, a comprehensive picture of inter-related mechanisms guiding muscle stem cell activity has still to be defined. Here, we reviewed the main regulatory networks determining satellite cell behavior. In particular, we focused on genetic and epigenetic mechanisms underlining satellite cell maintenance and commitment. Besides intrinsic regulations, we reported current evidences about the influence of environmental stimuli, derived from other cell populations within muscle tissue, on satellite cell biology.