Elevated CO2 Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation

Abstract

Muscle dysfunction often occurs in patients with chronic obstructive pulmonary diseases (COPD) and affects ventilatory and non-ventilatory skeletal muscles. We have previously reported that hypercapnia (elevated CO2 levels) causes muscle atrophy through the activation of the AMPKα2-FoxO3a-MuRF1 pathway. In the present study, we investigated the effect of normoxic hypercapnia on skeletal muscle regeneration. We found that mouse C2C12 myoblasts exposed to elevated CO2 levels had decreased fusion index compared to myoblasts exposed to normal CO2. Metabolic analyses of C2C12 myoblasts exposed to high CO2 showed increased oxidative phosphorylation due to increased fatty acid oxidation. We utilized the cardiotoxin-induced muscle injury model in mice exposed to normoxia and 10% CO2 for 21 days and observed that muscle regeneration was delayed. High CO2-delayed differentiation in both mouse C2C12 myoblasts and skeletal muscle after injury and was restored to control levels when cells or mice were treated with a carnitine palmitoyltransfearse-1 (CPT1) inhibitor. Taken together, our data suggest that hypercapnia leads to changes in the metabolic activity of skeletal muscle cells, which results in impaired muscle regeneration and recovery after injury.

Integrating Mechanisms of Exacerbated Atrophy and Other Adverse Skeletal Muscle Impact in COPD

“…As with studies on hypoxia, the levels of hypercapnia studied often exceed that seen in COPD patients, except perhaps under extreme conditions associated with acute exacerbations and/or in very severe patients needing lung transplant. Nonetheless, previous studies have shown that a PaCO 2 level of approximately 75 mmHg is associated with muscle atrophy (Jaitovich et al, 2015;Ceco et al, 2020), and in C2C12 muscle cell culture yields an increase in mitochondrial respiratory capacity that appears to be due to a compensatory upregulation of mitochondria (Ceco et al, 2020). Thus, whilst hypercapnia may contribute to the exacerbated muscle atrophy observed in COPD, it is possible that it may have a beneficial compensatory impact in limiting the severity of muscle mitochondrial respiratory capacity (Balnis et al, 2020b).…”

Hypercapnia in COPD: Causes, Consequences, and Therapy

“…The same research group also showed that AMPKα2 downregulated ribosomal biogenesis and thus decreased muscle protein synthesis, further negatively influencing the skeletal muscle turnover [ 106 ]. Furthermore, the regeneration of myoblasts is also impaired due to increased fatty acid oxidation caused by an enhanced rate of oxidative phosphorylation [ 8 ].…”

“…The prevalence of hypercapnia is around 30–50% in patients with very severe COPD (predicted forced expiratory volume in the first second (FEV 1 ) <30%) [ 5 ]. Although hypercapnia may be beneficial to mitigate pulmonary inflammation [ 6 ], there is an increasing amount of evidence suggesting that the deleterious effects outweigh the protective ones [ 7 , 8 , 9 , 10 ]. Hypercapnia causes alveolar epithelial dysfunction, which results in alveolar oedema formation and further deterioration in gas exchange [ 7 , 11 ].…”

Anti-Inflammatory Function of Fatty Acids and Involvement of Their Metabolites in the Resolution of Inflammation in Chronic Obstructive Pulmonary Disease

“…Given that carbohydrate catabolism is accompanied by the formation of large amounts of carbon dioxide, the use of fatty acids as an energy substrate contributes to less CO 2 production. Given the impaired CO 2 excretion in COPD, using fatty acids as an energy source may reduce some of the negative effects of the disease related to muscle dysfunction and shortness of breath [ 43 , 44 ]. And a diet low in carbohydrates but with the addition of medium chain triglycerides and predominantly monounsaturated fatty acids in the diet help improve pulmonary function in patients with COPD [ 45 ].…”