In this study we examined the contractile function, and protein composition of diaphragm muscle following 18 weeks of transverse aortic constriction (TAC) induced heart failure in mice Diaphragm function was characterized following 2 and 18 weeks of TAC. Hearts after 18 weeks of TAC had multiple indicators of systolic and diastolic dysfunction, demonstrated a reactivation of the fetal gene program and interstitial fibrosis. Contractile function of skinned diaphragm muscle preparations (~2.9 mm x 250 μM) was measured over a range of Ca concentrations at a sarcomere length of 2.3 μM. At each Ca concentration the maximum activated force was measured, as was the rate of force redevelopment following rapid release and re-stretch. The Ca sensitivity of force generation was significantly reduced in the 18 week TAC group compared to the sham mice and the two week TAC group. The Kf½ (Ca concentration at half maximum force generation) for the 18 week TAC group was 2.2 ± 0.17 μM while that for the sham group and 2 week TAC group were 1.86 ± 0.14 and 1.90 ± 0.15 μM respectively. In addition, the maximum Ca activated force was significantly lower for the 18 week TAC mice (22.1 ± 2.4 mN mm-2) compared to those from the sham group and 2 week TAC group, 30.5 ± 2.6 and 25.1 ± 2.2 mN mm-2, respectively. Western blotting indicates a significant increase in the presence of a high molecular weight protein complex containing TnT in diaphragm from the 18 week TAC group. There was also a reduction in the rate of cross-bridge cycling, in the diaphragm from the 2 and 18 week TAC as compared to sham. In the sham group, as Ca activated force increased there was a parallel increase in the rate of cross-bridge cycling. Comparatively, in the 2 and 18 week TAC groups, as force increased there was an initial increase in cross-bridge cycling but this reached an asymptote and then decreased before maximum force was reached. As a result, the rate of cross-bridge cycling in the diaphragms from the two treatment groups was significantly lower compared to those from the sham group for the latter half of the Ca activation curve. This reduction in cross-bridge cycling rates may be a compensatory mechanism to reduce the metabolic cost of contraction. However, this would reduce the rate of force development and therefore power generation by the muscle. The results of this study indicate that chronic hypertension initiates a series of changes in diaphragm contractility that have the potential to cause dysfunction in heart failure and may play a role in exercise intolerance and dyspnea, the chief complain from patients with heart failure.