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

Shin'ichi Takeda and colleagues show that loading of muscle results in nitric oxide creation and its conversion to peroxynitrite. The latter molecule then activates TRPV1 in the muscle, leading to increased cytoplasmic concentrations of calcium and activation of mTOR and, thus, muscle hypertrophy. They could replicate these effects without overload by treating mice with a TRPV1 agonist, suggesting a possible therapy for muscle wasting. 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 Ca 2+ concentration ([Ca 2+ ] 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 [Ca 2+ ] 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.