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Hypercapnia Suppresses Protein Anabolism in Skeletal Muscle Via AMPK-Driven Downregulation of Ribosomal Biogenesis
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A7141 - Hypercapnia Suppresses Protein Anabolism in Skeletal Muscle Via AMPK-Driven Downregulation of Ribosomal Biogenesis
Author Block: A. A. Jaitovich, T. Korponay, J. Balnis, T. Nguyen, H. Singer; Medicine and Molecular and Cell Physiology, Albany Medical College, Albany, NY, United States.
Rationale: Patients with Chronic Obstructive Pulmonary Disease (COPD) often develop high CO2 retention and skeletal muscle wasting. Both phenomena are predictive of higher mortality in these patients. Previous studies suggest that accelerated muscle catabolism is caused by hypercapnia via AMP-activated protein kinase (AMPK) activation and proteasome-mediated degradation. However, the effect of high CO2 on protein anabolism is not well-characterized. Methods: In this study, we investigated the role of hypercapnia on skeletal muscle protein synthesis. Western Blot analysis with C2C12 myotubes and C57 16-wees-old mice treated with the synthetic amino acid puromycin were used to interrogate protein anabolism in normo and hypercapnia. Activation of AMPK was demonstrated with phosphoantibodies targeting Thr172 and Acetyl-CoA Carboxylase Ser79. rtPCR was used to determine transcriptional activity of 45s-pre-RNA and specific siRNAs were used to determine the mechanistic role of the different mediators. Results: Hypercapnia-mediated AMPK phosphorylation occurs in a calcium-independent manner and is needed for decreased protein anabolism as measured by proteins’ puromycin incorporation. This process depends on depressed ribosomal biogenesis as reflected by the transcriptional activity of 45S-pre-RNA in hypercapnia and its preservation after silencing AMPK. The regulation of ribosomal biogenesis by AMPK does not require the participation of TIF1-A, which was shown to be relevant in glucose-deprivation anabolic suppression. Conclusions: Hypercapnia contributes to skeletal muscle wasting by down regulation protein synthesis, which is mediated by a calcium-independent activation of AMPK, depressed ribosomal biogenesis and not involving TIF1A.
Author Block: A. A. Jaitovich, T. Korponay, J. Balnis, T. Nguyen, H. Singer; Medicine and Molecular and Cell Physiology, Albany Medical College, Albany, NY, United States.
Rationale: Patients with Chronic Obstructive Pulmonary Disease (COPD) often develop high CO2 retention and skeletal muscle wasting. Both phenomena are predictive of higher mortality in these patients. Previous studies suggest that accelerated muscle catabolism is caused by hypercapnia via AMP-activated protein kinase (AMPK) activation and proteasome-mediated degradation. However, the effect of high CO2 on protein anabolism is not well-characterized. Methods: In this study, we investigated the role of hypercapnia on skeletal muscle protein synthesis. Western Blot analysis with C2C12 myotubes and C57 16-wees-old mice treated with the synthetic amino acid puromycin were used to interrogate protein anabolism in normo and hypercapnia. Activation of AMPK was demonstrated with phosphoantibodies targeting Thr172 and Acetyl-CoA Carboxylase Ser79. rtPCR was used to determine transcriptional activity of 45s-pre-RNA and specific siRNAs were used to determine the mechanistic role of the different mediators. Results: Hypercapnia-mediated AMPK phosphorylation occurs in a calcium-independent manner and is needed for decreased protein anabolism as measured by proteins’ puromycin incorporation. This process depends on depressed ribosomal biogenesis as reflected by the transcriptional activity of 45S-pre-RNA in hypercapnia and its preservation after silencing AMPK. The regulation of ribosomal biogenesis by AMPK does not require the participation of TIF1-A, which was shown to be relevant in glucose-deprivation anabolic suppression. Conclusions: Hypercapnia contributes to skeletal muscle wasting by down regulation protein synthesis, which is mediated by a calcium-independent activation of AMPK, depressed ribosomal biogenesis and not involving TIF1A.
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