AMPK activation attenuates S6K1, 4E-BP1, and eEF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractions.
Regulation of protein translation through Akt and the downstream mammalian target of rapamycin (mTOR) pathway is an important component of the cellular response to hypertrophic stimuli. It has been proposed that 5'-AMP-activated protein kinase (AMPK) activation during muscle contraction may limit the hypertrophic response to resistance-type exercise by inhibiting translational signaling. However, experimental manipulation of AMPK activity during such a stimulus has not been attempted. Therefore, we investigated whether AMPK activation can attenuate the downstream signaling response of the Akt/mTOR pathway to electrically stimulated lengthening muscle contractions. Extensor digitorum longus muscles (n = 8/group) were subjected to a 22-min bout of lengthening contractions by high-frequency sciatic nerve electrical stimulation (STIM) in young adult (8 mo) Fischer 344 x Brown Norway male rats. Forty minutes before electrical stimulation, rats were subcutaneously injected with saline or 5-aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR; 1 mg/g body wt), an AMPK activator. Stimulated and contralateral resting muscles were removed at 0, 20, and 40 min post-STIM, and AMPK, acetyl CoA carboxylase (ACC), Akt, eukaryotic initiation factor 4E-binding protein (4E-BP1), 70-kDa ribosomal protein S6 kinase (S6K1), and eukaryotic elongation factor 2 (eEF2) phosphorylations were assessed by Western blot. AICAR treatment increased (P < or = 0.05) post-STIM AMPK (Thr172) and ACC phosphorylation (Ser79/221), inhibited post-STIM S6K1 (Thr389) and 4E-BP1 (gel shift) phosphorylation, and elevated post-STIM eEF2 phosphorylation (Thr56). These findings suggest that translational signaling downstream of Akt/mTOR can be inhibited after lengthening contractions when preceded by AMPK activation and that energetic stress may be antagonistic to the hypertrophic translational signaling response to loaded muscle contractions.
Thomson
David M
DM
Human Performance Laboratory, Department of Exercise and Sport Science, East Carolina University, Greenville, NC 27858, USA.
Fick
Christopher A
CA
Gordon
Scott E
SE
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004558:Electric Stimulation; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000008:administration & dosage; D006984:Hypertrophy; D007279:Injections, Subcutaneous; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D020652:Peptide Elongation Factor 2 / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D012265:Ribonucleotides / Q000008:administration & dosage; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D012584:Sciatic Nerve / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D020536:Enzyme Activators; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D020652:Peptide Elongation Factor 2; D010750:Phosphoproteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide