Muscular diseases occur in all age groups and can cause serious physical disabilities. Duchenne muscular dystrophy (DMD) is one of the most severe forms of dystrophinopathy that occurs in younger age groups. The current trends among aging populations in developed countries indicate that sarcopenia, which is a muscular weakness involving muscular atrophy, will continue to be a serious problem in elderly persons. Our research has focused on identifying peptide therapeutics for these muscular diseases.
Two therapeutic approaches have significantly progressed in this field. The first approach centers on a mutation in the dystrophin gene that codes for an important structural protein within muscle tissue, dystrophin. This mutation accounts for about 20% of the congenital disease cases and is caused by nonsense mutations that introduce a premature termination codon (PTC) into the mRNA sequence. We have examined the utility of a dipeptidic antibiotic (+)-negamycin 1,1 which promotes PTC readthrough activity, and recently succeeded in developing more potent derivatives of 1 that displayed low levels of antimicrobial activity.2 These derivatives may be effective for the treatment of other genetic diseases caused by nonsense mutations. In an effort to increase the muscular mass in patients, we have focused on myostatin (growth differentiation factor 8, GDF-8), a member of the TGF-β protein family, which inhibits muscle differentiation and growth. Inhibitor peptides with about 20 amino acids in length have been developed as a second therapeutic approach. These peptides selectively inhibit myostatin signaling in a cell-based reporter assay and have resulted in improved muscular mass in mice upon direct intramuscular injection. These peptides could potentially enhance the muscular mass of elderly persons, treat muscular dystrophy, and improve cachexia in patients with cancer, chronic obstructive pulmonary disease (COPD), metabolic syndromes, and the muscular strength of astronauts.