MIF1 and MIF2 Myostatin Peptide Inhibitors as Potent Muscle Mass Regulators

The use of peptides as drugs has progressed over time and continues to evolve as treatment paradigms change and new drugs are developed. Myostatin (MSTN) inhibition therapy has shown great promise for the treatment of muscle wasting diseases. Here, we report the MSTN-derived novel peptides MIF1 (10-mer) and MIF2 (10-mer) not only enhance myogenesis by inhibiting MSTN and inducing myogenic-related markers but also reduce adipogenic proliferation and differentiation by suppressing the expression of adipogenic markers. MIF1 and MIF2 were designed based on in silico interaction studies between MSTN and its receptor, activin type IIB receptor (ACVRIIB), and fibromodulin (FMOD). Of the different modifications of MIF1 and MIF2 examined, _Ac-MIF1 and _Ac-MIF2-_NH2 significantly enhanced cell proliferation and differentiation as compared with non-modified peptides. Mice pretreated with _Ac-MIF1 or _Ac-MIF2-_NH2 prior to cardiotoxin-induced muscle injury showed more muscle regeneration than non-pretreated controls, which was attributed to the induction of myogenic genes and reduced MSTN expression. These findings imply that _Ac-MIF1 and _Ac-MIF2-_NH2 might be valuable therapeutic agents for the treatment of muscle-related diseases.