High CO₂ Downregulates Skeletal Muscle Protein Anabolism via AMP-activated Protein Kinase α2–mediated Depressed Ribosomal Biogenesis

Hypercapnia Regulates Gene Expression and Tissue Function

“…A transcriptomic study of mouse skeletal muscles revealed that normoxic hypercapnia altered the expression of genes involved in biological processes in diaphragm and soleus muscles (Shigemura et al, 2019). More recently, it has been shown to affect ribosomal biogenesis showing a marked reduction of ribosomal 45S pre-RNA in soleus and extensor digitorum longus (EDL) muscles isolated from mice exposed to hypercapnia and cultured myotubes exposed to high CO 2 as well as quadriceps muscles from hypercapnic patients (Jaitovich et al, 2015;Korponay et al, 2020). An unbiased proteomic analysis of EDL muscles in chronic hypercapniaexposed mice also indicated downregulation of components of "translation initiation" and "structural constituent of ribosome, " suggesting high CO 2 -mediated regulation of protein anabolism (Korponay et al, 2020).…”

“…The beneficial effects of hypercapnia have been reviewed in detail elsewhere over the past decades (Laffey and Kavanagh, 1999;Contreras et al, 2015). Contrastingly, in recent years, there is accumulating evidence that elevated CO 2 conditions are associated with adverse pathophysiological effects on the lung (Doerr et al, 2005;Vadasz et al, 2008;Gates et al, 2013;Shigemura et al, 2018;Bharat et al, 2020) and skeletal muscles (Jaitovich et al, 2015;Korponay et al, 2020). Recent discoveries suggest that high levels of CO 2 activate specific signaling pathways with deleterious consequences for organismal functions not only in mammals (Briva et al, 2007;O'Toole et al, 2009;Cummins et al, 2010;Wang et al, 2010;Welch et al, 2010;Vohwinkel et al, 2011;Oliver et al, 2012;Vadasz et al, 2012;Lecuona et al, 2013;Casalino-Matsuda et al, 2015;Dada et al, 2015;Selfridge et al, 2016;Kikuchi et al, 2017), but also the fly Drosophila melanogaster (Helenius et al, 2009;Vadasz et al, 2012), and the nematode Caenorhabditis elegans (Sharabi et al, 2009;Vadasz et al, 2012).…”

“…Increased ventilation stimulated by acute exposure to hypercapnia is also known to affect transcriptional regulations in respiratory muscles (Siafakas et al, 2001). More recent in vitro studies suggest the direct mechanisms by which hypercapnia regulates gene expression in different cell types and species (Helenius et al, 2009;Vohwinkel et al, 2011;Casalino-Matsuda et al, 2015Shigemura et al, 2018Shigemura et al, , 2019Korponay et al, 2020). However, a systems-level understanding of how hypercapnia effects are integrated into specific signaling pathways, and whether gene programs during hypercapnia are conserved in different cells/tissues and species still remains unclear.…”

Hypercapnia: An Aggravating Factor in Asthma

“…The lower tidal volumes during protective ventilation can lead to hypercapnia and an associated drop in pH resulting in hypercapnic respiratory acidosis that has been reported as a protective effect via the inhibition of the nuclear factor-κB (NF-κB) pathway, a pivotal transcription activator in inflammation and injury [ 7 , 22 ]. However, in recent years, it has become increasingly evident that elevated CO 2 acts as a gaso-signaling molecule, resulting in deleterious effects in various organs such as the lung [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ] and skeletal muscles [ 30 , 31 , 32 ] as well as innate immunity system [ 25 , 29 , 33 , 34 , 35 , 36 , 37 ]. In the lung, recent studies reported that high levels of CO 2 activate specific gene expression [ 26 , 38 , 39 , 40 ] and signal transduction pathways with adverse consequences on alveolar fluid clearance through Na, K-ATPase endocytosis via intracellular calcium- or extracellular signal-regulated kinase (ERK)-mediated AMP-activated protein kinase (AMPK)/protein kinase C-ζ/c-Jun-N-Terminal Kinase (JNK) signaling or soluble adenylyl cyclase-mediated protein kinase A-Iα signaling [ 24 , 41 , 42 , 43 , 44 , 45 , 46 ] and epithelial cell repair via AMPK-mediated Rac1-GTPase signaling, NF-κB pathways or miR-183-regulated mitochondrial dysfunction [ 28 , 47 , 48 , 49 ].…”

Antianabolic Effects of Hypercapnia: No Country for Strong Men

“…In this issue of the Journal , Korponay and colleagues (pp. 74–86) convincingly demonstrate that elevated levels of CO 2 decrease protein anabolism in skeletal muscles by decreasing ribosomal biogenesis (12). By performing a pilot study in human quadriceps muscle biopsies from normo- and hypercapnic patients with a history of lung disease, the authors identified a marked reduction of ribosomal 45S pre-RNA in muscles from the hypercapnic patient group, suggesting decreased protein translation.…”