Nfe2l1-mediated proteasome function controls muscle energy metabolism in obesity

Abstract

Muscle function is an important denominator of energy balance and metabolic health. Adapting the 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, using a multi-omics approach, we uncover that the distinct metabolic condition of obesity is associated with recalibration of the UPS in muscle. Interestingly, obesity is associated with the activation of the transcription factor Nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1), and loss of myocyte Nfe2l1 diminishes proteasomal activity and leads to hyperubiquitylation. Mice lacking Nfe2l1 display hormetic energy metabolism and resistance to diet-induced obesity, associated with a lean phenotype and muscle fiber type switching. In conclusion, we define a new adaptive role for UPS in remolding of muscle proteome and function, which is controlled by fine-tuning of proteasome function by Nfe2l1.

Growing strong muscle for better performance and weight loss

“…Loss of NFE2L1 in mice is associated with weaker muscles and lower physical capacity. Curiously, they display an enhanced energy metabolism and are more protected against highfat diet-induced obesity (Lemmer et al, 2023). We also observed that, in response to exercise, NFE2L1 is crucial for skeletal muscle recovery.…”

“…During the ERC PROTEOFIT project, our research has demonstrated that NFE2L1 plays a pivotal role as a regulator of proteasome genes in isolated muscle cells and transgenic mouse models (Lemmer et al, 2023). In a controlled cell culture environment designed for studying metabolism in a more isolated context, the absence of NFE2L1 results in the accumulation of ubiquitinated proteins (referred to as protein waste) due to impaired degradation by the proteasome.…”