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

Ermelinda Ceco,Lena Volpe,Navdeep S. Chandel,Samuel Weinberg,Lynn C. Welch,Jacob I. Sznajder,Ankit Bharat,Masahiko Shigemura,Diego Celli,Emilia Lecuona

doi:10.3389/fphys.2020.630910

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.

Highlights

Hypercapnia, elevated CO2 levels in tissues and blood, is seen in patients with inadequate alveolar gas exchange, such as chronic obstructive pulmonary disease (COPD), and it is associated with worse clinical outcomes (Yang et al, 2015; Fazekas et al, 2018)
We investigated the effect of elevated CO2 on skeletal muscle repair and found that hypercapnia induces a metabolic maladaptation, resulting in increased fatty acids β-oxidation and mitochondrial respiration leading to impaired myoblast differentiation
C2C12 myoblasts to high CO2 showed decreased proliferation as compared to myoblasts exposed to normal CO2, which is in agreement with our previous report, showing decreased proliferation of both epithelial cells and fibroblasts (Vohwinkel et al, 2011; Figure 1A)

Summary

Introduction

Hypercapnia, elevated CO2 levels in tissues and blood, is seen in patients with inadequate alveolar gas exchange, such as chronic obstructive pulmonary disease (COPD), and it is associated with worse clinical outcomes (Yang et al, 2015; Fazekas et al, 2018). Even though COPD skeletal muscle dysfunction may affect both ventilatory and limb muscles, the latter are usually more severely affected (Barreiro and Jaitovich, 2018). A multicenter European-based study showed that quadriceps muscle dysfunction occurred in approximately one-third of the COPD patients, even at the early stages of their disease (Seymour et al, 2010; Barreiro and Jaitovich, 2018). The prevalence of muscle weakness among the patients did not significantly correlate with disease severity but was associated with body mass index, airflow obstruction, dyspnea, exercise capacity, and dyspnea scores (Seymour et al, 2010; Barreiro and Jaitovich, 2018)

Methods

Results

Conclusion