I. L. Lemmer, D. T. Haas, N. Willemsen, S. Kotschi, I. Toksoez, E. Gjika, S. Khani, M. Rohm, N. Diercksen, P. B. H. Nguyen, M. P. Menden, D. T. Egu, J. Waschke, S. Larsen, T. Ma, Z. Gerhart-Hines, S. Herzig, K. Dyar, N. Krahmer, A. Bartelt, L. Matta, F. Valdivieso-Rivera, C. Jethwa, A. Mena Gomez
Muscle function is an important denominator of energy metabolism and metabolic health. Adapting the myocyte proteome to energetic challenges, in response to diet or fasting, is facilitated by programs of proteostasis, but the adaptive role of the ubiquitin-proteasome system (UPS) in muscle remains unclear. Here, we show that myocyte Nuclear factor erythroid derived 2,-like 1 (Nfe2l1, also known as Nrf1) is a key regulator of skeletal muscle proteostasis and function. In mice and humans, Nfe2l1 is highly expressed in skeletal myocytes, and its loss diminishes proteasomal activity and leads to hyperubiquitylation. Mice lacking myocyte Nfe2l1 display muscle fiber type switching and insulin resistance when fed a high-fed diet. Nfe2l1 protects myocytes from ferroptosis, which is enhanced in the presence of excess lipids. In conclusion, we define a new adaptive role for the Nfe2l1-ubiquitin proteasome system in the control of skeletal muscle function and energy metabolism.