Histidine decarboxylase inhibition attenuates cancer-associated muscle wasting.

Abstract

Cancer cachexia is a multifactorial syndrome involving muscle and fat wasting, inflammation, and metabolic dysfunction. Across cancer subtypes, pancreatic cancer has one of the highest cachexia incidence rates at ∼80%. Given the advanced age of most pancreatic cancer patients, we sought to query cancer-associated muscle wasting using an age-matched murine model. We found that histamine and histamine decarboxylase (HDC) activity were specifically elevated in the muscles of aged tumor-bearing mice. We further found that (1) wasting stimuli induced histamine production and enhanced HDC activity; (2) exogenous histamine was sufficient to induce atrophy-associated gene expression; (3) inhibition of HDC activity by α-fluoromethylhistidine (FMH) protected against atrophy; (4) treatment of tumor-bearing mice with FMH rescued muscle wasting; and (5) a calcineurin inhibitor was able to rescue histamine-associated increases in calcium/atrogene signaling. In summary, we present a novel metabolic pathway that has significant implications for the treatment of cachectic cancer patients.