IL‐33 Receptor Gene Deletion and Skeletal Muscle Abnormalities in a Mouse Model of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive, incurable disease of the pulmonary vasculature, leading to high pulmonary vascular resistance and right ventricular failure. In addition, PAH patients show marked skeletal muscle abnormalities that may develop before right heart pathology. Thus, skeletal muscle dysfunction may be more closely related to the primary pathology of PAH than originally thought. We hypothesized that IL‐33, recently implicated in the cardiopulmonary pathogenesis of PAH, is also requisite for skeletal muscle maladaptation. Using adult C57BL/6J mice, we induced PAH with 3 wks of chronic hypoxia (FiO 2 0.10) and weekly subcutaneous injections (20 mg . kg −1 ) of the VEGF receptor kinase inhibitor Su5416 (SuHx). SuHx was applied in both wild‐type (WT) and IL‐33 receptor gene ablated (ST2 −/− ) mice. Further, vehicle control (DMSO) WT mice were generated using the same injection volume and schedule and were housed in normoxia (CON). Mitochondrial function was measured in permeabilized diaphragm and soleus using a titration protocol that included maximal ADP‐stimulated respiration ( J O2max ) and non‐phosphorylating electron transport system capacity (ETS). Diaphragm J O2max was reduced in WT‐SuHx vs. WT‐CON (85±26 vs 162±62 pmol.s.mg‐ −1 ; p <0.05), but not in ST2 −/− ‐SuHx (148±102 pmol.s.mg‐ −1 ; p >0.72 vs WT‐CON). Diaphragm ETS followed a similar pattern in WT‐SuHx vs WT‐CON (90±29 vs 167±63 pmol.s.mg‐ −1 ; p <0.05), and was not different in ST2 −/− ‐SuHx vs WT‐CON (152±104 pmol.s.mg‐ −1 ; p >0.73). Flux control ratios ( J O2max /ETS) were not different between groups ( p >0.75). Soleus J O2max was reduced in both WT‐SuHx and ST2 −/− ‐SuHx vs WT‐CON (70±33 and 86±38 vs 140±40 pmol.s.mg‐ −1 ; p <0.05). Soleus ETS was also reduced in WT‐SuHx and ST2 −/− ‐SuHx vs WT‐CON (68±24 and 86±38 vs 140±30 pmol.s.mg‐ −1 ; p <0.05). Similar to diaphragm, soleus flux control ratios were not different between groups ( p >0.73). The SuHx model showed a profound reduction in skeletal muscle mitochondrial oxidative capacity, suggestive of similar abnormalities to those reported in patients with PAH. As the flux control ratios were not different in SuHx, reduced mitochondrial volume‐density was a more likely mechanism, rather than a deficit in the quality of integrated function between electron transport and phosphorylation. Global gene deletion of the IL‐33 receptor (ST2) prevented diaphragm mitochondrial deficits in SuHx, but soleus muscle was less well‐protected. Our data strengthen the hypothesis that inflammatory cytokines, such as IL‐33, may play a critical role in skeletal muscle maladaptation to PAH. Support or Funding Information This research was supported by the US Department of Veterans Affairs.