Curcumin Improves Exercise Performance of Mice with Coronary Artery Ligation Induced HFrEF: Nrf2 and Antioxidant Mechanisms in Skeletal Muscle

A hallmark of chronic heart failure with low ejection fraction (HFrEF) is exercise intolerance. We hypothesized that reduced expression of nuclear factor E2-related factor 2 (Nrf2) in skeletal muscle contributes to impaired exercise performance. We further hypothesized that curcumin (Cur), a Nrf2 activator, would preserve or increase exercise capacity in HF. Experiments were carried out in mice with coronary artery ligation-induced HFrEF. Cur was deliveried by a subcutaneous osmotic minipump at a dose of 50 mg/kg/day for 8 weeks. In vivo, in situ, and in vitro experiments were employed to evaluate exercise capacity, muscle function, and molecular mechanisms. We found that: (1) the maximal speed, running distance to exhaustion, and limb grip force were significantly lower in HFrEF mice compared to sham. Cur-treated HF mice displayed enhanced exercise performance compared to vehicle-treated HF mice; (2) Both soleus (Sol) and extensor digitorum longus (EDL) muscles of HFrEF mice exhibited reduced force and rapid fatigue, which were ameliorated by Cur. (3) Protein expression of Nrf2, HO-1, SOD2, myogenin, and MyoD were significantly lower but total ubiquitinated proteins, MURF1, and Atrogen-1 were higher in Sol and EDL of HFrEF compared to sham mice, whereas these alterations in Nrf2 signaling and antioxidant defenses in HFrEF were attenuated by Cur. Cur had no effect on cardiac function per se in mice with severe HFrEF. These data suggest that impaired Nrf2 signaling intrinsic to skeletal muscle contributes to exercise intolerance in HFrEF. Skeletal muscle Nrf2 should be considered as a novel therapeutic target in severe HF.