Article ; Online: Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization.
Journal of cachexia, sarcopenia and muscle
2024 Volume 15, Issue 2, Page(s) 631–645
Abstract: Background: Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic ... ...
| Abstract | Background: Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions. Methods: Experimental mice were exposed to prolonged normobaric hypoxic air (15% pO Results: Chronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P < 0.001; Soleus: 11.5% reduction in weight, P < 0.001) and weakness (10.0% reduction in peak-isometric torque, P < 0.001), along with impaired muscle regeneration characterized by diminished myofibre cross-sectional areas, increased fibrosis (P < 0.001), and incomplete strength recovery (92.3% of pre-injury levels, P < 0.05). HIF-2α stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi, P < 0.01). HIF-2α ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi, P < 0.01), while HIF-1α ablation did not have the same effect. HIF-2α stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF-2α. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase, P < 0.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi, P < 0.05), suggesting their therapeutic potential for alleviating chronic hypoxia-associated muscle atrophy. Conclusions: Chronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia. |
|---|---|
| MeSH term(s) | Animals ; Mice ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Hypoxia ; Indans ; Lisinopril ; Muscle, Skeletal/metabolism ; Muscular Atrophy/etiology ; Sulfones |
| Chemical Substances | Basic Helix-Loop-Helix Transcription Factors ; Indans ; Lisinopril (E7199S1YWR) ; PT2385 ; Sulfones ; endothelial PAS domain-containing protein 1 (1B37H0967P) |
| Language | English |
| Publishing date | 2024-02-09 |
| Publishing country | Germany |
| Document type | Journal Article |
| ZDB-ID | 2586864-0 |
| ISSN | 2190-6009 ; 2190-5991 |
| ISSN (online) | 2190-6009 |
| ISSN | 2190-5991 |
| DOI | 10.1002/jcsm.13436 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.