SEX DIFFERENCES AND PROTEOMIC PROFILING OF DIAPHRAGM WEAKNESS IN CHRONIC HEART FAILURE

Abstract

Inspiratory dysfunction occurs in patients with chronic heart failure (CHF). The diaphragm is the primary inspiratory muscle, and diaphragm abnormalities likely contribute to the dyspnea and exercise intolerance that these patients experience. Animal models show that CHF causes diaphragm weakness, but it remains unclear whether disease effects and mechanisms of weakness are sex‐specific. We conducted the current study to test whether CHF effects on diaphragm function and morphology are sex‐specific and to explore putative mechanisms for diaphragm abnormalities via proteomics. We performed myocardial infarction or sham surgery on Sprague Dawley rats. We focused our efforts on animals with severe CHF, determined by 1) transmural infarct ≥ 35% of left ventricle + septal area and 2) right ventricle hypertrophy. We assessed diaphragm isometric contractile function in vitro, fiber type and cross sectional area, and global label free proteomics with mass spectrometry. CHF decreased diaphragm maximal tetanic isometric specific force (N/cm2) by ~20% in both males and females (n = 5–8 per group; P < 0.05). However, the effects on isometric twitch specific force were sex‐specific. CHF decreased twitch specific force (N/cm2) by ~30% (P < 0.05) in males, with no effect in females. There were no effects of disease on fiber type distribution or cross‐sectional area in either sex. Our preliminary proteomic results did not reveal any obvious changes in protein abundance that could explain the decrease in maximal diaphragm force in CHF. For instance, CHF (males) increased the relative quantity of myosin binding protein C fast‐type and troponin T slow isoform and decreased myosin light chain kinase‐2 and phosphorylase b kinase (P < 0.01, false‐discovery rate 1%). In females, our proteomics showed no changes in relative protein quantity with CHF. Overall, our data show that CHF effects on the diaphragm are generally similar between sexes, except for twitch specific force. Our preliminary findings from proteomics suggest that post‐translational modifications, rather than changes in relative quantity, are the main mechanisms underlying diaphragm weakness in CHF.Support or Funding InformationFunding support from NIH R01 HL130318