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

Abstract

Skeletal muscle atrophy occurs in aging and pathological conditions, including cancer, diabetes and AIDS. 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. 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, 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.

EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short-term mechanical unloading

“…nNOS translocation has previously been associated with increased FoxO3a activation and MuRF-1 activation and muscle atrophy during ground hindlimb unloading (42) and during 91 days of spaceflight (33). In contrast, a new publication indicates that nNOS is necessary in triggering an anabolic signaling pathway involving Nox4 and mTOR, which responds to overloading and regulates muscle hypertrophy (15). Furthermore, nitric oxide and NF-B were also found to be essential for stretch-induced proliferation of myoblasts (40).…”

“…Previously, nitric oxide synthase inhibition was shown to regulate muscle hypertrophy and fiber-type shift in response to overloading (15,38). In addition, inhibition or genetic ablation of nNOS substantially reduced proteolysis and muscle fiber atrophy during mechanical unloading (42).…”

“…Furthermore, knockout of the nNOS gene has been recently shown to elicit myopathy and a reduction in contractile force (29). In addition, new data from Ito et al (15) demonstrate that nNOS activation of the NADPH oxidase isoform Nox4 contributes to hypertrophy when skeletal muscle is overloaded. These data suggest in total that nNOS may serve as an effector of dynamic changes in mechanical loading, regardless of whether loading is increased or decreased.…”

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…Different major signaling cascades such as PI-3K, MAPKs, Ca 2ϩ -calmodulin-calcineurin-NFAT, glycogen synthase kinase (GSK), and AMP activated kinase (AMPK) are downstream effectors of mechanotransduction (86) (FIGURE 4). Mechanosensing in skeletal muscle involves multiple components and spans from integrins, focal adhesion complexes (FAC), stretch-activated calcium-and sodium-permeable membrane ion channels, caveolin-3 and the caveolin-3-associated nNOS, the sarcodystroglycan complex, intermediate filaments, and a number of mechanosensitive sarcomeric proteins, as well as mechanosignaling via the IGF-I growth factor (76,86,346,390,391,641,652,686,687,754) signaling (FIGURE 4). In addition, external forces on surface membrane receptors, such as integrins and cadherins, might act at distance and promote coordinated changes in nuclear structures via a hard-wired network including structural actin and specialized nuclear anchoring structures (349,754).…”

Methodological issues limit interpretation of negative effects of satellite cell depletion on adult muscle hypertrophy

“…A very small increase or even reduction in crosssectional area (CSA) accompanied by an increase in the number of fibers has previously been reported in a few studies (Ferry et al, 2014;Joanne et al, 2012;Parsons et al, 2004), but to our knowledge not for observation periods as short as 2 weeks, and even most long-term studies report a robust hypertrophy (Ballak et al, 2016(Ballak et al, , 2015Dunn et al, 1999Dunn et al, , 2000Guerci et al, 2012;Ito et al, 2013;Johnson and Klueber, 1991;White et al, 2009). Although fiber splitting was not studied in either of the two papers, and is not a well-understood phenomenon, we agree that it is a reasonable speculation about the causes of the poor hypertrophy observed in the SC+OL+ muscles by (since we observed more robust hypertrophy, we think it less likely to be a significant issue in our own work).…”