Abstract:
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Numerous investigations provided strong evidence that the modulation of the activity of specific cell signaling pathways has an important role in neuromuscular disease progression and the development of therapies. We analyzed the role of PI3K-AKT and MAPK pathways in the regulation of muscle atrophy and slow-to-fast phenotype transition using the animal hindlimb unloading (HU) model. For that purpose, we studied, in rat slow soleus and fast EDL muscles, the time-course of anabolic PI3KAKT- mTOR, catabolic PI3K-AKT-FOXO and MAPK signaling pathway activation after 7, 14, and 28 days of HU. Moreover, we performed chronic low frequency soleus electrostimulation during HU in order to maintain exclusively phenotype and so to determine more precisely the role of these signaling pathways in the modulation of muscle mass. HU induced a down-regulation of the anabolic AKT, mTOR, p70S6K, 4EBP1 and GSK3_ targets and an up-regulation of the catabolic FOXO1 and MURF1 targets correlated with soleus muscle atrophy. Unexpectedly, soleus electrostimulation maintained p70S6K, 4E-BP1, FOXO1 and MURF1 to control levels, but failed to reduce muscle atrophy. HU decreased ERK phosphorylation while electrostimulation enabled to maintain ERK phosphorylation similar to control level. Moreover, slow-to-fast myosin heavy chain phenotype transition and up-regulated glycolytic metabolism were prevented by soleus electrostimulation during HU. Taken together, our data demonstrated that the processes responsible for gradual muscle disuse involved PI3-AKT and MAPK pathways in the imbalance between protein synthesis and degradation, and the regulation of contractile phenotype and metabolic profile. Electrostimulation during HU was able to restore PI3K-AKT and ERK pathway activation without counteracting the decrease in mass, suggesting the implication of other signaling pathways in disuse muscle plasticity. Thus, advances in our understanding of the signaling pathways may help to identify novel therapeutic targets for muscular diseases.
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