Hidden enzyme may explain muscle loss tied to cancer treatment and aging
A study published in the Journal of Clinical Investigation (April 25) identified the enzyme MESH1 as a key driver of cancer cachexia, a condition causing muscle loss, weakness, and fatigue in up to 50% of advanced cancer patients and associated with poorer survival. Researchers found that MESH1 breaks down coenzyme A (CoA), which is vital for energy production and cellular stress protection, and that its levels were elevated in muscle tissues from affected patients. The study suggests that targeting MESH1 could offer a new therapeutic approach, as experiments in fruit flies showed that excess MESH1 depleted protective molecules and triggered ferroptosis, a form of cell death linked to oxidative damage.
Researchers say the discovery of MESH1 provides a potential new therapeutic target to intervene in cancer related muscle loss. Experts note that the same pathway may also help explain muscle fragility in aging, where reduced strength increases risks such as falls and loss of independence. The study authors, including Chi and Hong Wen Tang, highlight that future research will test whether blocking MESH1 can prevent or reverse muscle wasting, with contributions from multiple co-authors across Duke institutions.
Researchers found that MESH1 has a dual role, as it not only breaks down coenzyme A (CoA) but was previously known to degrade NADPH, a key molecule that protects cells from stress and damage. This dual activity gives the enzyme significant influence over cellular survival and death by regulating multiple metabolic pathways. However, scientists still do not fully understand how MESH1 coordinates these processes, and they suggest that AI based protein engineering could help create targeted variants of the enzyme to better study its specific functions.
The study identifies MESH1 as a promising drug target, suggesting that inhibiting it could help preserve coenzyme A (CoA) levels and protect muscle tissue during cancer treatments such as chemotherapy and radiation. Researchers note that cancer cachexia remains challenging to manage, as it is driven by metabolic and inflammatory changes rather than insufficient nutrition, making standard nutritional support largely ineffective. Currently, no drugs are approved in the United States specifically for preventing cancer related muscle wasting. The research was supported by multiple funding bodies, including the National Institutes of Health, Duke Cancer Institute, the U.S. Department of Defense, and several Singapore-based research and health agencies.
