title: Regulation of Akt-mTOR, ubiquitin-proteasome and autophagy-lysosome pathways in response to formoterol administration in rat skeletal muscle.
abstract: Administration of β2-agonists triggers skeletal muscle anabolism and hypertrophy. We investigated the time course of the molecular events responsible for rat skeletal muscle hypertrophy in response to 1, 3 and 10 days of formoterol administration (i.p. 2000μg/kg/day). A marked hypertrophy of rat tibialis anterior muscle culminated at day 10. Phosphorylation of Akt, ribosomal protein S6, 4E-BP1 and ERK1/2 was increased at day 3, but returned to control level at day 10. This could lead to a transient increase in protein translation and could explain previous studies that reported increase in protein synthesis following β2-agonist administration. Formoterol administration was also associated with a significant reduction in MAFbx/atrogin-1 mRNA level (day 3), suggesting that formoterol can also affect protein degradation of MAFbx/atrogin1 targeted substrates, including MyoD and eukaryotic initiation factor-3f (eIF3-f). Surprisingly, mRNA level of autophagy-related genes, light chain 3 beta (LC3b) and gamma-aminobutyric acid receptor-associated protein-like 1 (Gabarapl1), as well as lysosomal hydrolases, cathepsin B and cathepsin L, was significantly and transiently increased after 1 and/or 3 days, suggesting that autophagosome formation would be increased in response to formoterol administration. However, this has to be relativized since the mRNA level of Unc-51-like kinase1 (Ulk1), BCL2/adenovirus E1B interacting protein3 (Bnip3), and transcription factor EB (TFEB), as well as the protein content of Ulk1, Atg13, Atg5-Atg12 complex and p62/Sqstm1 remained unchanged or was even decreased in response to formoterol administration. These results demonstrate that the effects of formoterol are mediated, in part, through the activation of Akt-mTOR pathway and that other signaling pathways become more important in the regulation of skeletal muscle mass with chronic administration of β2-agonists.
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, F-42023 Saint-Etienne, France.
authors.forename: Olivier Roger
authors.initials: OR
authors.lastname: Joassard
authors.forename: Adel
authors.initials: A
authors.lastname: Amirouche
authors.forename: Yann Simon
authors.initials: YS
authors.lastname: Gallot
authors.forename: Marine Maud
authors.initials: MM
authors.lastname: Desgeorges
authors.forename: Josiane
authors.initials: J
authors.lastname: Castells
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Durieux
authors.forename: Phanélie
authors.initials: P
authors.lastname: Berthon
authors.forename: Damien Gilles
authors.initials: DG
authors.lastname: Freyssenet
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000068759:Formoterol Fumarate; D005786:Gene Expression Regulation / Q000187:drug effects; D006984:Hypertrophy; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004983:Ethanolamines; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D025801:Ubiquitin; D010768:Phosphoserine; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D000068759:Formoterol Fumarate
keywords: -subunit of the Gq protein; -subunit of the inhibitory G protein; -subunit of the stimulatory G protein; 4E-BP1; Actb; Akt-mTOR pathway; Atg; Autophagy; BCL2/adenovirus E1B interacting protein 3; BSA; Bnip3; COPD; CREB; EDL; ERK; Epac; FoxO3; GAS; Gabarapl1; Gαi, α; Gαq, α; Gαs, α; Hprt; Hypertrophy; IGF-1; IRS-1; LC3b; MAFbx/atrogin-1; MEF2; MuRF1; PE; PGC-1α; PI3K; PKA; Rap; SOL; TA; TBS; TFEB; TSC2; Ubiquitin-proteasome; Ulk1; actin beta; autophagy-related; bovine serum albumin; cAMP response element binding protein; chronic obstructive pulmonary disease; eIF3-f; eukaryotic initiation factor 3 subunit f; eukaryotic initiation factor 4E-binding protein 1; exchange protein activated directly by cAMP; extensor digitorum longus; extracellular signal-regulated kinase; forkhead box O3; gamma-aminobutyric acid receptor-associated protein; gastrocnemius; hypoxanthine guanine phosphoribosyl transferase; insulin growth factor-1; insulin receptor substrate-1; light chain 3 beta; mTOR; mammalian target of rapamycin; muscle RING finger-1; myocyte enhancer factor 2; p62/Sqstm1; peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α; phosphatidylethanolamine; phosphatidylinositol 3-kinase; protein kinase A; ras-related protein; ribosomal protein S6; rpS6; sequestosome 1; soleus; tibialis anterior; transcription factor EB; tris-buffered saline; tuberous sclerosis complex 2; unc-51-like kinase 1.; β(2)-agonist