Identification of novel small molecule Adiponectin receptor agonists and evaluation of their effects on skeletal muscle

Abstract

Skeletal muscle atrophy imposes a huge socio-economical burden due to exacerbating disease conditions like cancer, CVD, CKD, and diabetes. Hence, finding treatment for skeletal muscle atrophy is an urgent need, as currently available methods, including dietary supplementation and exercise, may not be achieved in required magnitude and intensity in bedridden or in patients on life-support. We screened natural product-inspired compounds for evaluating AdipoR agonist activity and myogenic potential, as adiponectin pathways play a pivotal role in mitigating metabolic disorders and documented myogenic functions. We screened 10 compounds, of which 4 candidates showed myogenic potential from femtomolar concentrations and upregulated adiponectin signaling at sub-picomolar concentrations. Of 4 candidates, three were evaluated in the LPS-TNF-α-induced in vitro atrophy model, and two candidates effectively mitigate atrophy in C2C12 myotubes.