Activation of calcium signaling through Trpv1 by nNOS and peroxynitrite as a key trigger of skeletal muscle hypertrophy

Skeletal muscle atrophy occurs in aging and pathological conditions, including cancer, diabetes and AIDS(1). Treatment of atrophy is based on either preventing protein-degradation pathways, which are activated during atrophy, or activating protein-synthesis pathways, which induce muscle hypertrophy(2). Here we show that neuronal nitric oxide synthase (nNOS) regulates load-induced hypertrophy by activating transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The overload-induced hypertrophy was prevented in nNOS-null mice. nNOS was transiently activated within 3 min after overload. This activation promoted formation of peroxynitrite, a reaction product of nitric oxide with superoxide(3), which was derived from NADPH oxidase 4 (Nox4). Nitric oxide and peroxynitrite then activated Trpv1, resulting in an increase of intracellular Ca2+ concentration ([Ca2+](i)) that subsequently triggered activation of mammalian target of rapamycin (mTOR). Notably, administration of the TRPV1 agonist capsaicin induced hypertrophy without overload and alleviated unloading- or denervation-induced atrophy. These findings identify nitric oxide, peroxynitrite and [Ca2+](i) as the crucial mediators that convert a mechanical load into an intracellular signaling pathway and lead us to suggest that TRPV1 could be a new therapeutic target for treating muscle atrophy.