Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization.

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% pO2, 1 atm, 2 weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia-inducible factors HIF-1α and HIF-2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin-induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC-specific HIF-2α knockout mice, and mice treated with HIF-2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia- and HIF-2α-dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann-Whitney U tests. 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.

The kynurenine pathway in HIV, frailty and inflammaging.

Kynurenine (Kyn) is a circulating tryptophan (Trp) catabolite generated by enzymes including IDO1 that are induced by inflammatory cytokines such as interferon-gamma. Kyn levels in circulation increase with age and Kyn is implicated in several age-related disorders including neurodegeneration, osteoporosis, and sarcopenia. Importantly, Kyn increases with progressive disease in HIV patients, and antiretroviral therapy does not normalize IDO1 activity in these subjects. Kyn is now recognized as an endogenous agonist of the aryl hydrocarbon receptor, and AhR activation itself has been found to induce muscle atrophy, increase the activity of bone-resorbing osteoclasts, decrease matrix formation by osteoblasts, and lead to senescence of bone marrow stem cells. Several IDO1 and AhR inhibitors are now in clinical trials as potential cancer therapies. We propose that some of these drugs may be repurposed to improve musculoskeletal health in older adults living with HIV.

Pendrin-null mice develop severe hypokalemia following dietary Na+ and K+ restriction: role of ENaC.

Pendrin is an intercalated cell Cl-/[Formula: see text] exchanger thought to participate in K+-sparing NaCl absorption. However, its role in K+ homeostasis has not been clearly defined. We hypothesized that pendrin-null mice will develop hypokalemia with dietary K+ restriction. We further hypothesized that pendrin knockout (KO) mice mitigate urinary K+ loss by downregulating the epithelial Na+ channel (ENaC). Thus, we examined the role of ENaC in Na+ and K+ balance in pendrin KO and wild-type mice following dietary K+ restriction. To do so, we examined the relationship between Na+ and K+ balance and ENaC subunit abundance in K+-restricted pendrin-null and wild-type mice that were NaCl restricted or replete. Following a NaCl-replete, K+-restricted diet, K+ balance and serum K+ were similar in both groups. However, following a Na+, K+, and Cl--deficient diet, pendrin KO mice developed hypokalemia from increased K+ excretion. The fall in serum K+ observed in K+-restricted pendrin KO mice was enhanced with ENaC stimulation but eliminated with ENaC inhibition. The fall in serum K+ observed in K+-restricted pendrin KO mice was enhanced with ENaC stimulation but eliminated with ENaC inhibition. However, reducing ENaC activity also reduced blood pressure and increased apparent intravascular volume contraction, since KO mice had lower serum Na+, higher blood urea nitrogen and hemoglobin, greater weight loss, greater metabolic alkalosis, and greater NaCl excretion. We conclude that dietary Na+ and K+ restriction induces hypokalemia in pendrin KO mice. Pendrin-null mice limit renal K+ loss by downregulating ENaC. However, this ENaC downregulation occurs at the expense of intravascular volume.NEW & NOTEWORTHY Pendrin is an apical Cl-/[Formula: see text] exchanger that provides renal K+-sparing NaCl absorption. The pendrin-null kidney has an inability to fully conserve K+ and limits renal K+ loss by downregulating the epithelial Na+ channel (ENaC). However, with Na+ restriction, the need to reduce ENaC for K+ balance conflicts with the need to stimulate ENaC for intravascular volume. Therefore, NaCl restriction stimulates ENaC less in pendrin-null mice than in wild-type mice, which mitigates their kaliuresis and hypokalemia but exacerbates volume contraction.