An Adiponectin Receptor Agonist Promotes Muscle Growth in Rats
The research community remains very interested in finding novel ways to promote muscle growth with minimal side effects. Therapies that inhibit myostatin or upregulate follistatin signaling are under development, and follistatin gene therapies have been available via medical tourism for some years. But most of the research community is focused on pharmacology, the use of small molecules to influence muscle metabolism. As an example of this type of work, researchers here report on a small molecule that mimics adiponectin signaling to promote muscle growth in rats.
Skeletal muscle atrophy is a hallmark of ageing and chronic diseases, yet effective pharmacotherapies remain unavailable. Adiponectin signalling through receptors AdipoR1 and AdipoR2 regulates skeletal muscle metabolism, regeneration and oxidative capacity, but the therapeutic use of adiponectin is limited by its large size and complex multimeric structure. Small-molecule AdipoR agonists, therefore, represent an attractive therapeutic strategy.
Here, we report the discovery and pharmacological characterization of medicarpin, a previously described osteogenic phytoalexin and its water-soluble sodium salt (Med), as dual AdipoR1/R2 agonists, and demonstrate the efficacy of Med in vitro and in rodent models of skeletal muscle atrophy. Med enhanced myogenic differentiation, evidenced by increasing myotube formation and expression of MyoD, myogenin and MyHC. Med also enhanced oxidative capacity by increasing fatty acid oxidation and Med-treated cells showed elevated oxidative fibre markers.
Oral administration of Med significantly attenuated muscle atrophy in both rat models, evidenced by improved muscle morphology, suppressed atrogenes, enhanced myogenic markers and increased muscle adiponectin expression and corresponding downstream signalling. Med markedly improved muscle function, including grip strength, wire hanging, rotarod performance, and toe-spread ability of denervated limbs.