Diminished muscle growth in the obese Zucker rat following overload is associated with hyperphosphorylation of AMPK and dsRNA-dependent protein kinase

Abstract

Previous data have suggested that insulin-resistant skeletal muscle may exhibit a diminished ability to undergo hypertrophy and that this result may be mediated, at least in part, from decrements in mammalian target of rapamycin (mTOR) signaling (Katta A, Kundla S, Kakarla SK, Wu M, Fannin J, Paturi S, Liu H, Addagarla HS, Blough ER. Am J Physiol Regul Integr Comp Physiol 299: R1666-R1675, 2010). Herein, we attempt to extend these observations by determining if this attenuation in muscle growth is associated with alterations in AMP-activated protein kinase (AMPK) signaling, an upstream mediator of mTOR, and changes in the activation of dsRNA-dependent protein kinase (PKR), which functions as an inhibitor of protein synthesis and potential mediator of protein degradation. Compared with that observed in lean Zucker (LZ) rats, the phosphorylation of AMPKα at Thr172 was higher after 3 wk of overload in the insulin-resistant obese Zucker (OZ) soleus (P < 0.05). This change in AMPKα phosphorylation was accompanied by increases in the amount of phosphorylated PKR (Thr446), elevations in the PKR-dependent phosphorylation of eukaryotic initiation factor (eIF)-2α (Ser51), augmented p38 MAP kinase (Thr180/Tyr182) phosphorylation, and increases in the amount of protein ubiquitination (P < 0.05). Taken together, these results suggest that the diminished hypertrophic response we observe in the OZ rat may be mediated, at least in part, by the hyperactivation of AMPK- and PKR-related signaling.

The Role of AMPK in the Regulation of Skeletal Muscle Size, Hypertrophy, and Regeneration

“…Several subsequent studies have reported negative associations between AMPK phosphorylation or activity and skeletal muscle growth. Indeed, impaired overload hypertrophy in obese rats [ 85 , 86 ], attenuated mTOR phosphorylation in metabolic syndrome patients [ 87 ], myotube hypertrophy during differentiation [ 88 ], myostatin inhibition of eEF2 and protein synthesis in myotubes [ 89 ], and differences in hypertrophy with varied ladder-climbing protocols in rats [ 90 ] are all associated inversely with AMPK activity.…”

β-Hydroxy-β-methylbutyrate (HMB) prevents sepsis-induced diaphragm dysfunction in mice

“…Several papers have suggested that HMB administration may alter factors that regulate one or more steps required for protein synthesis (Kornasio et al, 2009. Smith et al, 2005 Katta et al, 2012). HMB also appears to influence the function of key proteolytic pathways, including the proteasome and caspase proteolytic pathways (Supinski and Callahan, 2006, Eley et al 2006, Smith et al 2005).…”