A quantitative redox proteome of the human muscle response to exercise
- 1Department of Cancer Biology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute
Abstract
Reactive oxygen species (ROS) regulate protein function through reversible cysteine oxidation. In human skeletal muscle, exercise-induced ROS initiates adaptations such as mitochondrial biogenesis, increased insulin sensitivity, and hypertrophy. However, specific protein targets of ROS regulation during exercise remain unclear owing to longstanding challenges in analyzing redox proteomes in vivo. We applied cysteine derivatization and multiplexed proteomics to map muscle protein cysteine oxidation in humans during exercise. The OxiMuscle dataset quantifies reversible modifications across 9,177 unique cysteine sites on 2,782 proteins, comprising 17,492 individual cysteine site measurements in young men undergoing three types of exercise, providing the first comprehensive, site-resolved and quantitative analysis of the exercise-regulated redox cysteine proteome in humans. We systematically define cysteine oxidation targets regulated by at least one form of exercise, many of which reside in proteins with established roles in muscle physiology. Among these sites is a redox-regulated cysteine on the autophagy receptor protein p62. We demonstrate that reversible oxidation of this cysteine regulates p62-mediated autophagy upon myotube contraction and mouse muscle adaptation to exercise in vivo. Together, these results define a redox-driven mechanism linking exercise-induced autophagy to muscle adaptation. More broadly, our findings offer a comprehensive resource on redox-signaling networks in human muscle, accessible at http://oximuscle-alb-1899330623.us-east-1.elb.amazonaws.com/.
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BibTeX
@misc{lei2026quantitative,
title = {{A quantitative redox proteome of the human muscle response to exercise}},
author = {Y. Lei and J. J. Petrocelli and A. Reddy and C. Henriquez-Olguin and N. Burger and S. Shin and B. Zhang and T. Covington and M. Waldeck-Weiermair and J. Zhang and S. M. Wei and T. E. Jensen and C. T. Voldstedlund and C. S. Carl and B. Kiens and E. A. Richter and E. T. Chouchani},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751463},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751463v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A quantitative redox proteome of the human muscle response to exercise
AU - Y. Lei
AU - J. J. Petrocelli
AU - A. Reddy
AU - C. Henriquez-Olguin
AU - N. Burger
AU - S. Shin
AU - B. Zhang
AU - T. Covington
AU - M. Waldeck-Weiermair
AU - J. Zhang
AU - S. M. Wei
AU - T. E. Jensen
AU - C. T. Voldstedlund
AU - C. S. Carl
AU - B. Kiens
AU - E. A. Richter
AU - E. T. Chouchani
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751463
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751463v1
AB - Reactive oxygen species (ROS) regulate protein function through reversible cysteine oxidation. In human skeletal muscle, exercise-induced ROS initiates adaptations such as mitochondrial biogenesis, increased insulin sensitivity, and hypertrophy. However, specific protein targets of ROS regulation during exercise remain unclear owing to longstanding challenges in analyzing redox proteomes in vivo. We applied cysteine derivatization and multiplexed proteomics to map muscle protein cysteine oxidation in humans during exercise. The OxiMuscle dataset quantifies reversible modifications across 9,177 unique cysteine sites on 2,782 proteins, comprising 17,492 individual cysteine site measurements in young men undergoing three types of exercise, providing the first comprehensive, site-resolved and quantitative analysis of the exercise-regulated redox cysteine proteome in humans. We systematically define cysteine oxidation targets regulated by at least one form of exercise, many of which reside in proteins with established roles in muscle physiology. Among these sites is a redox-regulated cysteine on the autophagy receptor protein p62. We demonstrate that reversible oxidation of this cysteine regulates p62-mediated autophagy upon myotube contraction and mouse muscle adaptation to exercise in vivo. Together, these results define a redox-driven mechanism linking exercise-induced autophagy to muscle adaptation. More broadly, our findings offer a comprehensive resource on redox-signaling networks in human muscle, accessible at http://oximuscle-alb-1899330623.us-east-1.elb.amazonaws.com/.
ER -