Heart failure patients often have reduced exercise tolerance, which can significantly affect their quality of life. Studies by researchers at the University of Nebraska Medical Center have now found that curcumin, one of the main components in the spice turmeric, improves exercise performance and grip strength in mice with heart failure and low ejection fraction (HFrEF).
Curcumin (Cur) activates nuclear factor E2-related factor 2 (Nrf2), a protein that regulates the expression of antioxidant enzymes, and results from the mouse studies suggest that Nrf2 in skeletal muscle may represent a promising therapeutic target for severe heart failure in humans. “Given that many Nrf2 activators are being developed for clinical applications, we believe this strategy is practicable,” the researchers reported in a paper titled “Curcumin improves exercise performance of mice with coronary artery ligation induced HFrEF: Nrf2 and antioxidant mechanisms of action,” which was published in the Journal of Applied Physiology.
Heart failure affects about 6.5 million people in the U.S. and is responsible for about one in eight deaths, wrote lead author Ahmed M Wafi, Ph.D., and colleagues at the University of Nebraska Medical Center Department of Cellular and Integrative Physiology. People with heart failure have reduced function of the left ventrical that pumps oxygenated blood to the body, and one of the major hallmarks of chronic heart failure with low ejection fraction is exercise intolerance. “Exercise intolerance represents a major clinical manifestation of this syndrome, profoundly impacting patients’ quality of life and prognosis,” the team pointed out.
Low exercise capacity in HFrEF patients is linked with muscle abnormalities, and with enhanced oxidative stress. “It is well established that oxidative stress is systemically increased in the HFrEF,” the authors stated. “Excessive free radicals not only exacerbate the failing heart but also injure peripheral organs, skeletal muscle being one of the major victims … in skeletal muscles from HFrEF animals, redox homeostasis is poorly maintained and excess ROS [reactive oxygen species] accumulates, leading to contractile dysfunction and muscle atrophy, and subsequent fatigue and exercise intolerance.”
Studies have also shown that the upregulation of antioxidant enzymes in skeletal muscle represents the principal mechanism by which exercise capacity is boosted in human heart failure patients and animals that undergo chronic exercise training. What isn’t known is why antioxidants are downregulated in HF patients.
Nrf2 is a master transcription factor regulator that regulates antioxidant enzyme expression, but the researchers say that as far as they know there haven’t been any studies evaluating Nrf2 in the skeletal muscle of humans or animals with HF. The team hypothesized that suppressed Nrf2 signaling may play a role in impaired expression of antioxidant enzymes in the skeletal muscle of mice with HFrEF. They tested whether curcumin, a polyphenol found in turmeric—and which is known to activate Nrf2—might improve exercise performance in the animals.
The team first confirmed that mice with surgically induced heart failure had reduced exercise tolerance. The animals couldn’t run as far or as fast on the treadmill as control mice, and they also had reduced limb grip force. There was a progressive decrease in exercise capacity with time after surgery, suggesting that skeletal muscle and/or cardiac function were deteriorating over time, the researchers reported.
One group of mice with HFrEF was then treated using a daily dose of curcumin for 12 weeks, and another group received no active therapy. The results showed that while exercise capacity continued to decrease over time in the control mice, curcumin therapy was associated with improved exercise capacity, and this was linked with increased expression of Nrf2 in muscle fibers, and higher levels of antioxidant enzymes. Interestingly, curcumin also improved exercise capacity in animals that didn’t have heart failure, indicating that the compound’s effects on skeletal muscle isn’t limited to heart failure. It’s not the first time that curcumin’s effects on skeletal muscle function has been noted, the authors stated. “… a growing body of evidence indicates that Cur can limit skeletal muscle atrophy in several pathological conditions via enhancing antioxidant defense by stimulating the Nrf2 signaling pathway.”
The team says their data are the first, to their knowledge, to demonstrate that impaired Nrf2 signaling contributes to skeletal myopathy, and that activation of Nrf2 represents “a promising therapeutic strategy to improve exercise capacity in the setting of HFrEF … These data suggest that activation of Nrf2 in skeletal muscle may represent a novel therapeutic strategy to improve HFrEF patients’ quality of life.”