title: Electrostimulation during hindlimb unloading modulates PI3K-AKT downstream targets without preventing soleus atrophy and restores slow phenotype through ERK.
abstract: Our aim was to analyze the role of phosphatidylinositol 3-kinase (PI3K)-AKT and MAPK signaling pathways in the regulation of muscle mass and slow-to-fast phenotype transition during hindlimb unloading (HU). For that purpose, we studied, in rat slow soleus and fast extensor digitorum longus muscles, the time course of anabolic PI3K-AKT-mammalian target of rapamycin, catabolic PI3K-AKT-forkhead box O (FOXO), and MAPK signaling pathway activation after 7, 14, and 28 days of HU. Moreover, we performed chronic low-frequency soleus electrostimulation during HU to maintain exclusively contractile phenotype and so to determine more precisely the role of these signaling pathways in the modulation of muscle mass. HU induced a downregulation of the anabolic AKT, mammalian target of rapamycin, 70-kDa ribosomal protein S6 kinase, 4E-binding protein 1, and glycogen synthase kinase-3β targets, and an upregulation of the catabolic FOXO1 and muscle-specific RING finger protein-1 targets correlated with soleus muscle atrophy. Unexpectedly, soleus electrostimulation maintained 70-kDa ribosomal protein S6 kinase, 4E-binding protein 1, FOXO1, and muscle-specific RING finger protein-1 to control levels, but failed to reduce muscle atrophy. HU decreased ERK phosphorylation, while electrostimulation enabled the maintenance of ERK phosphorylation similar to control level. Moreover, slow-to-fast myosin heavy chain phenotype transition and upregulated glycolytic metabolism were prevented by soleus electrostimulation during HU. Taken together, our data demonstrated that the processes responsible for gradual disuse muscle plasticity in HU conditions involved both PI3-AKT and MAPK pathways. Moreover, electrostimulation during HU restored PI3K-AKT activation without counteracting soleus atrophy, suggesting the involvement of other signaling pathways. Finally, electrostimulation maintained initial contractile and metabolism properties in parallel to ERK activation, reinforcing the idea of a predominant role of ERK in the regulation of muscle slow phenotype.
authors.affiliation: University Lille Nord de France, EA 4488, Laboratoire d'Activité Physique, Muscle et Santé, USTL, F-59655 Villeneuve d'Ascq, France. erwan.dupont@univ-lille1.fr
authors.forename: Erwan
authors.initials: E
authors.lastname: Dupont
authors.forename: Caroline
authors.initials: C
authors.lastname: Cieniewski-Bernard
authors.forename: Bruno
authors.initials: B
authors.lastname: Bastide
authors.forename: Laurence
authors.initials: L
authors.lastname: Stevens
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000502:physiology; D004558:Electric Stimulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D019417:Hindlimb Suspension / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018995:Myosin Heavy Chains / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D014176:Protein Biosynthesis / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013979:Tibial Nerve / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000071161:Forkhead Box Protein O1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D051858:Forkhead Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018995:Myosin Heavy Chains; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C546845:mTOR protein, rat