NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS
Naoki Suzuki, Norio Motohashi, Akiyoshi Uezumi, So-ichiro Fukada, Tetsuhiko Yoshimura, Yasuto Itoyama, Masashi Aoki, Yuko Miyagoe-Suzuki, Shin’ichi Takeda
Naoki Suzuki, Norio Motohashi, Akiyoshi Uezumi, So-ichiro Fukada, Tetsuhiko Yoshimura, Yasuto Itoyama, Masashi Aoki, Yuko Miyagoe-Suzuki, Shin’ichi Takeda
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Research Article

NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS

Abstract

Forkhead box O (Foxo) transcription factors induce muscle atrophy by upregulating the muscle-specific E3 ubiquitin ligases MuRF-1 and atrogin-1/MAFbx, but other than Akt, the upstream regulators of Foxos during muscle atrophy are largely unknown. To examine the involvement of the dystrophin glycoprotein complex (DGC) in regulation of Foxo activities and muscle atrophy, we analyzed the expression of DGC members during tail suspension, a model of unloading-induced muscle atrophy. Among several DGC members, only neuronal NOS (nNOS) quickly dislocated from the sarcolemma to the cytoplasm during tail suspension. Electron paramagnetic resonance spectrometry revealed production of NO in atrophying muscle. nNOS-null mice showed much milder muscle atrophy after tail suspension than did wild-type mice. Importantly, nuclear accumulation of dephosphorylated Foxo3a was not evident in nNOS-null muscle, and neither MuRF-1 nor atrogin-1/MAFbx were upregulated during tail suspension. Furthermore, an nNOS-specific inhibitor, 7-nitroindazole, significantly prevented suspension-induced muscle atrophy. The NF-κB pathway was activated in both wild-type and nNOS-null muscle during tail suspension. We also show that nNOS was involved in the mechanism of denervation-induced atrophy. We conclude that nNOS/NO mediates muscle atrophy via regulation of Foxo transcription factors and is a new therapeutic target for disuse-induced muscle atrophy.

Authors

Naoki Suzuki, Norio Motohashi, Akiyoshi Uezumi, So-ichiro Fukada, Tetsuhiko Yoshimura, Yasuto Itoyama, Masashi Aoki, Yuko Miyagoe-Suzuki, Shin’ichi Takeda

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Figure 6

7NI alleviates muscle atrophy during tail suspension.

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7NI alleviates muscle atrophy during tail suspension. (A) Soleus muscle ...
(A) Soleus muscle weight of wild-type ground control and wild-type tail-suspended mice with (+7NI) or without 7NI (+oil). Oil or 7NI (50 mg/kg/d) was injected daily into the abdominal cavity of the mice during 2-week tail suspension. Values (muscle weight/body weight) are expressed as percent of wild-type oil-injected muscles after 14-day tail suspension (n = 5–10 per group; *P < 0.05, Mann-Whitney). (B) mRNA levels of MuRF-1 and atrogin-1/MAFbx (n = 4) in muscle from wild-type ground control and wild-type tail-suspended mice with or without 7NI were quantified by real-time RT-PCR (*P < 0.05, Mann-Whitney). (C) The amount of total Foxo3a, dephosphorylated Foxo3a, and intranuclear Foxo3a (n = 4) were analyzed by western blotting, and band densities were normalized to α-tubulin (*P < 0.05, Mann-Whitney).