HUWE1 in Skeletal Muscle Prevents Muscle Fatigue via Maintaining Iron and Calcium Homeostasis.

ABSTRACT: Iron is critical to optimal athletic performance because of its role in energy metabolism, oxygen transport, and acid-base balance. However, the precise mechanism how skeletal muscle maintains iron homeostasis during exercise remains enigmatic. Here, it is demonstrated that the HECT-domain containing ubiquitin ligase E3 Huwe1 (also known as MULE or ARF-BP1) in skeletal muscle is suppressed upon exhausted exercise. Loss of Huwe1 in skeletal muscle restrains the exercise performance of Huwe1 conditional knockout (cKO) mice, accompanied with pronounced oxidative stress. Mechanistically, Huwe1 depletion stabilizes c-Myc protein, leading to upregulated sarcolipin (Sln) expression with inhibited SarcoEndoplasmic Reticulum Calcium ATPase (SERCA) activity, and downregulated ferroportin (Fpn, also

SUBMITTER: Jiao H 

PROVIDER: S-EPMC12822411 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature