Min Li, Brittany Alexandre McKeon, Sue Gu, Ram Raj Prasad, Hui Zhang, Sushil Kumar, Suzette Riddle, David C. Irwin, Kurt R. Stenmark
University of Colorado Anschutz Medical Campus.
United States
International Journal of Molecular Sciences
Int J Mol Sci 2024; 25:
DOI: 10.3390/ijms252111600
Abstract
Pulmonary hypertension (PH) significantly impairs exercise capacity and the quality of life in patients, which is influenced by dysfunctions in multiple organ systems, including the right ventricle, lungs, and skeletal muscles. Recent research has identified metabolic reprogramming and mitochondrial dysfunction as contributing factors to reduced exercise tolerance in PH patients. In this study, we investigated the therapeutic potential of enhancing mitochondrial function through the activation of the mitochondrial deacetylase SIRT3, using SIRT3 activator Honokiol combined with the SIRT3 co-factor nicotinamide adenine dinucleotide (NAD), in a Sugen/Hypoxia-induced PH rat model. Our results show that Sugen/Hypoxia-induced PH significantly impairs RV, lung, and skeletal muscle function, leading to reduced exercise capacity. Treatment with Honokiol and NAD notably improved exercise endurance, primarily by restoring SIRT3 levels in skeletal muscles, reducing proteolysis and atrophy in the gastrocnemius, and enhancing mitochondrial complex I levels in the soleus. These effects were independent of changes in cardiopulmonary hemodynamics. We concluded that targeting skeletal muscle dysfunction may be a promising approach to improving exercise capacity and overall quality of life in PH patients.
Category
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Animal Models of Pulmonary Vascular Disease and Therapy
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes