ABSTRACT
BACKGROUND: Age-related muscle atrophy is characterized by increased oxidative stress, diminished Akt enzymatic function, and reduced phosphorylation of the mammalian target of rapamycin (mTOR), which can be attenuated by chronic acetaminophen ingestion. Here we hypothesize that age-related impairments in Akt/mTOR function are associated with reduced protein translational signaling, and that these changes, if present, can be attenuated by acetaminophen treatment. RESULTS: Compared to 6- and 27-month old animals, the expression of the mTOR-complex proteins raptor and GßL and the phosphorylation of tuberin/TSC2 (Thr1462) were reduced in the soleus muscles of very aged rats (33 months old). These changes in Akt/mTOR pathway signaling proteins were in turn associated with decreased phosphorylation of S6 kinase p85S6K (Thr412) and eukaryotic translation initiation factor-4E (eIF4E) binding protein-1 (4EBP1, Thr37/46), reduced phosphorylation of S6 ribosomal protein (Ser235/236), and increased inhibition of eIF4E by binding to 4EBP1. Age-associated alterations in the Akt/mTOR pathway signaling and in the phosphorylation of the stress-responsive eIF2α protein were attenuated by chronic acetaminophen treatment (30 mg/kg body weight per day). Ex vivo incubation of adult muscles with hydrogen peroxide mimicked the age-related decreases seen in eIF4E and 4EBP1 phosphorylation, whereas the inclusion of acetaminophen in the muscle bath attenuated this effect. CONCLUSION: Aging is associated with impairments in the regulation of proteins thought to be important in controlling mRNA translation, and acetaminophen may be useful for the treatment of age-related muscle atrophy by reducing oxidative stress.
Subject(s)
Acetaminophen/pharmacology , Aging/drug effects , Aging/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Protein Biosynthesis/drug effects , Signal Transduction/drug effects , Animals , Carrier Proteins/metabolism , Eukaryotic Initiation Factor-2/metabolism , Eukaryotic Initiation Factor-4E/metabolism , In Vitro Techniques , Intracellular Signaling Peptides and Proteins , Male , Models, Biological , Phosphoproteins/metabolism , Phosphorylation/drug effects , Rats , Ribosomal Protein S6/metabolism , Ribosomal Protein S6 Kinases/metabolism , TOR Serine-Threonine Kinases/metabolism , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/metabolismABSTRACT
Increased phosphorylation of the 70-kDa ribosomal S6 kinase (p70S6k) signaling is strongly correlated with the degree of muscle adaptation following exercise. Herein we compare the phosphorylation of p70S6k, Akt, and mammalian target of rapamycin (mTOR) in the tibialis anterior (TA) muscles of lean and obese Zucker rats following a bout of eccentric exercise. Exercise increased p70S6k (Thr389) phosphorylation immediately after (33.3+/-7.2%) and during [1 h (24.0+/-14.9%) and 3 h (24.6+/-11.3%)] recovery in the lean TA and at 3 h (33.5+/-8.0%) in the obese TA Zucker rats. mTOR (Ser2448) phosphorylation was elevated in the lean TA immediately after exercise (96.5+/-40.3%) but remained unaltered in the obese TA. Exercise increased Akt (Thr308) and Akt (Ser473) phosphorylation in the lean but not the obese TA. These results suggest that insulin resistance is associated with alterations in the ability of muscle to activate p70S6k signaling following an acute bout of exercise.
