Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene MSS51, which is an inhibitor of skeletal muscle mitochondrial metabolism. Despite the potential importance of MSS51 in the pathophysiology of obesity and musculoskeletal disease, how MSS51 is regulated is not entirely understood. Site-1 Protease (S1P) is a Golgi-resident protease that is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle and mitochondrial function are unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial metabolism. Disruption of S1P in mouse skeletal muscle and cultured myofibers leads to a reduction in MSS51 expression, increased muscle mass, and increased mitochondrial oxygen consumption. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing MSS51, suggesting that S1P inhibits mitochondrial metabolism by regulating the expression of MSS51. Furthermore, S1P suppression enhances TGF-β signaling via the AKT pathway, potentially explaining muscle hypertrophy in S1P deficient mice. The discovery of S1P as a regulator of mitochondrial metabolism and muscle mass expands our understanding of TGF-β signaling and suggests this protease could be a target for therapeutic intervention in muscle. ### Competing Interest Statement Rita Brookheart and Brian Finck are inventors on a pending U.S. non-provisional patent application titled, Methods and Compositions for Improving Exercise Endurance, Performance, or Tolerance (Application Number: 16/732,740). Rita Brookheart holds a provisional patent related to this work (provisional patent application no. 63/370,712).