The IGF‐I splice variant MGF increases progenitor cells in ALS, dystrophic, and normal muscle

Abstract

The effects of muscle splice variants of insulin-like growth factor I (IGF-I) on proliferation and differentiation were studied in human primary muscle cell cultures from healthy subjects as well as from muscular dystrophy and ALS patients. Although the initial numbers of mononucleated progenitor cells expressing desmin were lower in diseased muscle, the E domain peptide of IGF-IEc (MGF) significantly increased the numbers of progenitor cells in healthy and diseased muscle. IGF-I significantly enhances myogenic differentiation whereas MGF E peptide blocks this pathway, resulting in an increased progenitor (stem) cell pool and thus potentially facilitating repair and maintenance of this postmitotic tissue.

Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblasts or primary muscle stem cells

“…Addition of MGF peptide to C 2 C 12 muscle myoblasts increased proliferation and retarded differentiation, even in the presence of anti-IGF-I receptor antibodies (31). Similar proliferation/differentiation results were also obtained in studies with primary human muscle myoblasts derived from explant cultures (2) and with porcine satellite cells (25). MGF also has a documented role in enhancing human muscle myoblast migration, possibly through activating matrix fibrinolytic and metalloproteinase systems (21).…”

Satellite Cells and the Muscle Stem Cell Niche

“…MGF promotes myoblast proliferation in vitro (26,578). However, the existence of MGF and its functions in vivo remain controversial (discussed in Ref.…”

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

“…The differential biological effects of the synthetic Ec-peptide compared with mature IGF-I peptide, such as cell proliferation versus differentiation, and the lack of suppression of the synthetic E-peptide bioactivity after blocking (mature) IGF-I signaling with IGF-IR neutralizing antibodies, makes it tempting to postulate that the Ec-peptide acts via a different receptor (28,135,145). However, concerns have been raised about the effectiveness of the IGF-IR neutralizing antibodies to block IGF-I signaling, since they could internalize and, in this way, even activate the receptor, or change its localization, thus facilitating an E-peptide action (38).…”

“…Although, by the general consensus, IGF-I is thought to exert its biological actions predominantly through mature peptide, differential biological activities have been reported for the different IGF-I isoforms (propeptides), or for their E-peptides, exogenously administrated or overexpressed in various in vivo (28,29,36,(132)(133)(134) and in vitro models (20,27,(31)(32)(33)135,136), implying that there are peptides other than the IGF-I ligand that also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects (31,36).…”