Therapeutic potential of adiponectin and adipoRon in Duchenne muscular dystrophy

Persistent and severe inflammation exacerbates disease progression in Duchenne muscular dystrophy (DMD). Adiponectin (ApN) is a hormone abundantly secreted by adipocytes, which exhibits insulin-sensitizing, fat-burning and anti-inflammatory properties. We have previously shown that ApN potently protects muscle against inflammation and injury in mdx mice, a model of DMD. As every peptide, ApN has to be injected, while AdipoRon, a recently discovered synthetic small-molecule, which is an agonist of ApN receptors may be given orally. Here we investigated whether ApN retains its anti-inflammatory properties in DMD myotubes and whether this action may be reproduced by AdipoRon. Primary cultures of myotubes from DMD patients and age- and sex-matches controls were performed (n=7 independent cultures from 4 different patients for each group; myoblasts were obtained from the French Telethon Myobank-AFM). These myotubes were challenged by an inflammatory stimulus (to mimic the DMD inflammatory status) and treated or not by ApN/AdipoRon. ApN downregulated gene expression of TNFα, a pro-inflammatory cytokine (p < 0.01) and of Iκb, an inhibitor of NF-κB (p < 0.05) while upregulating mRNA abundance of Il-6, an anti-inflammatory cytokine (p<0.05) in control as well as in DMD myotubes. Silencing selected genes further indicated that these anti-inflammatory effects were mediated by AdipoR1, the most abundant ApN receptor in the muscle and by the AMPK-SIRT1-PGC-1α signaling pathway in control and DMD myotubes; PGC-1α is a transcriptional activator, which regulates energy metabolism and suppresses inflammation. Eventually, AdipoRon reduced TNFα mRNAs (p < 0.05) and increased Il-6 mRNAs (p < 0.001) in both DMD and control myotubes challenged by an inflammatory stimulus. ApN retains its anti-inflammatory effects in human myotubes obtained from DMD patients. AdipoRon reproduces this protection. These results could open new perspectives in the management of muscular disease