Skeletal Muscle Dysfunction in Experimental Pulmonary Hypertension.

Area of Science:

• Cardiovascular Research
• Skeletal Muscle Physiology
• Molecular Biology

Background:

• Pulmonary arterial hypertension (PAH) is a severe, progressive disease with limited treatment options.
• Skeletal muscle dysfunction significantly impacts exercise tolerance in PAH patients.
• Understanding the molecular mechanisms of muscle dysfunction in PAH is crucial for developing new therapies.

Purpose of the Study:

• To investigate skeletal muscle changes in an experimental model of severe pulmonary hypertension (PH).
• To explore the role of FoxO1 and fiber-type specification in PH-induced muscle dysfunction.

Main Methods:

• Utilized the Sugen/hypoxia (SU/Hx) rat model to induce severe PH.
• Assessed exercise endurance, muscle fiber markers, sarcomeric aggregates, and FoxO1 levels.
• Analyzed transcriptomic profiles of diaphragm and extensor digitorum longus muscles.
• Conducted studies in L6 rat myoblasts to examine FoxO1's role in fiber-type differentiation.

Main Results:

• The SU/Hx model exhibited a ~50% decrease in exercise endurance.
• Significant increase in type II muscle fiber markers and sarcomeric aggregates observed.
• Elevated FoxO1 levels in soleus muscle, alongside soleus atrophy.
• Distinct transcriptomic alterations in diaphragm and extensor digitorum longus muscles.
• In vitro studies confirmed FoxO1's influence on muscle fiber-type specification.

Conclusions:

• Skeletal muscle dysfunction, characterized by aggregate formation and FoxO1-mediated fiber-type shifts, is a key feature of experimental PH.
• These molecular changes likely contribute to the impaired exercise tolerance seen in PH.
• Targeting FoxO1 pathways may offer a therapeutic strategy for PAH-associated muscle dysfunction.