Abstract
To test the hypothesis that p38α-MAPK plays a critical role in the regulation of E3 ligase expression and skeletal muscle atrophy during unloading, we used VX-745, a selective p38α inhibitor. Three groups of rats were used: non-treated control (C), 3 days of unloading/hindlimb suspension (HS), and 3 days HS with VX-745 inhibitor (HSVX; 10 mg/kg/day). Total weight of soleus muscle in HS group was reduced compared to C (72.3 ± 2.5 vs 83.0 ± 3 mg, respectively), whereas muscle weight in the HSVX group was maintained (84.2 ± 5 mg). The expression of muscle RING-finger protein-1 (MuRF1) mRNA was significantly increased in the HS group (165%), but not in the HSVX group (127%), when compared with the C group. The expression of muscle-specific E3 ubiquitin ligases muscle atrophy F-box (MAFbx) mRNA was increased in both HS and HSVX groups (294% and 271%, respectively) when compared with C group. The expression of ubiquitin mRNA was significantly higher in the HS (423%) than in the C and HSVX (200%) groups. VX-745 treatment blocked unloading-induced upregulation of calpain-1 mRNA expression (HS: 120%; HSVX: 107%). These results indicate that p38α-MAPK signaling regulates MuRF1 but not MAFbx E3 ligase expression and inhibits skeletal muscle atrophy during early stages of unloading.
Highlights
IntroductionSkeletal muscle has a large amount of plasticity, responding to the decrease in activity caused by a variety of conditions (immobilization, microgravity, prolonged bed rest, denervation, etc.) by atrophy, declined muscle fiber diameter, loss of protein content, decreased specific force, and increased fatigability [1,2,3]
Skeletal muscle has a large amount of plasticity, responding to the decrease in activity caused by a variety of conditions by atrophy, declined muscle fiber diameter, loss of protein content, decreased specific force, and increased fatigability [1,2,3]
We examined whether activation of p38α MAP kinase at the early stages of unloading regulated the expression of muscle-specific E3 ubiquitin ligases muscle atrophy F-box (MAFbx) and muscle RING-finger protein-1 (MuRF1)
Summary
Skeletal muscle has a large amount of plasticity, responding to the decrease in activity caused by a variety of conditions (immobilization, microgravity, prolonged bed rest, denervation, etc.) by atrophy, declined muscle fiber diameter, loss of protein content, decreased specific force, and increased fatigability [1,2,3]. The expression of muscle-specific E3 ubiquitin ligases muscle atrophy F-box (MAFbx) and muscle RING-finger protein-1 (MuRF1) is regulated via activity of the ubiquitin–proteasome pathway. The majority of previous studies focused on the role of Forkhead box protein O (FoxO) phosphorylation/de-phosphorylation by Akt in the regulation of E3 ubiquitin ligase expression [6]. Different regulatory mechanisms can play the most critical role in the regulation of MuRF1 expression
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