Stem cell-mediated muscle regeneration is enhanced by local isoform of insulin-like growth factor 1Â
Faculty of Computing, Health and Science
School of Exercise, Biomedical and Health Science
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 MLC/mIgf-1 transgenic muscles was accompanied by elevated bone marrow stem cell production in response to distal trauma. Regenerating MLC/mIgf-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. Skeletal muscle regeneration involves the activation of quiescent satellite cells, which participate in the reconstitution of damaged tissues. Recent studies have identified another source of muscle stem cells (SC), named side population (SP) on the basis of their Hoechst dye exclusion properties (1). Originating in the bone marrow (2), these cells can home to various tissues, differentiating into multiple cell types (3–8). Although in lethally irradiated mice, bone marrow-derived SCs replenish the depleted satellite cell pool and subsequently incorporate effectively into exercised skeletal muscle (9), less is known about the ability of bone-marrow-derived SCs to ameliorate muscle damage under more clinically relevant conditions. Indeed, the transplantation of bone marrow-derived SCs into the mdx dystrophic mouse model had a limited impact on muscle cell replacement (10), suggesting that the poor recruitment of circulating SCs is one of the limiting factors for tissue repair (10, 11). Subsequent studies in nonirradiated mice have identified resident stem-like cell populations in skeletal muscle distinct from satellite cells (12–14), which undergo myogenesis by means of myocyte-mediated inductive interactions (15). We have previously reported that postmitotic expression of a local isoform of insulin-like growth factor 1 (mIGF-1) induces myocyte hypertrophy (16), increases mass and strength of postnatal muscle, and preserves regenerative capacity in senescent and dystrophic mice (17–19). In the present study, enhanced muscle regeneration was accompanied by increased recruitment of marked, transplanted bone marrow SCs to sites of muscle injury after lethal irradiation. In nonirradiated MLC/mIgf-1 transgenic mice, muscle injury expanded the SP compartment in the bone marrow. Transgenic animals also had elevated levels of cells coexpressing markers of SC lineage and myogenic commitment at sites of muscle damage. When isolated from regenerating muscles, these cells exhibited accelerated myogenic differentiation in culture and readily induced muscle-specific markers in a subset of cocultured bone marrow cells. These results establish mIGF-1 as a potent regenerative agent, increasing bone marrow and local SC pools and providing a mechanistic explanation for the dramatic effects of supplemental MLC/mIgf-1 transgene expression on muscle mass and integrity both in vitro and in vivo.