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

Area of Science:

• Biomedical Science
• Skeletal Muscle Physiology
• Metabolic Regulation

Background:

• Muscle dysfunction is common in chronic obstructive pulmonary diseases (COPD).
• Hypercapnia (elevated CO2) previously shown to cause muscle atrophy via the AMPKα2-FoxO3a-MuRF1 pathway.
• The impact of hypercapnia on skeletal muscle regeneration remains unclear.

Purpose of the Study:

• To investigate the effect of normoxic hypercapnia on skeletal muscle regeneration.
• To elucidate the metabolic changes associated with hypercapnia in muscle cells.
• To identify potential therapeutic targets for mitigating hypercapnia-induced muscle impairment.

Main Methods:

• Exposure of mouse C2C12 myoblasts and mice to normoxic hypercapnia (10% CO2).
• Assessment of myoblast fusion index and differentiation.
• Cardiotoxin-induced muscle injury model in mice.
• Metabolic analysis of C2C12 myoblasts.
• Treatment with a carnitine palmitoyltransferase-1 (CPT1) inhibitor.

Main Results:

• Hypercapnia decreased myoblast fusion index and delayed skeletal muscle regeneration after injury.
• Metabolic analyses revealed increased oxidative phosphorylation and fatty acid oxidation in hypercapnic myoblasts.
• Muscle differentiation and regeneration were impaired under hypercapnia.
• CPT1 inhibition restored normal differentiation and regeneration in both cell cultures and injured mice.

Conclusions:

• Normoxic hypercapnia impairs skeletal muscle regeneration by altering cellular metabolism, specifically increasing fatty acid oxidation.
• The carnitine palmitoyltransferase-1 (CPT1) pathway is implicated in hypercapnia-induced muscle dysfunction.
• Inhibiting CPT1 may represent a therapeutic strategy to improve muscle recovery in conditions involving hypercapnia.