Sweet taste receptor signaling and skeletal muscle proteostasis - PROJECT SUMMARY Loss of skeletal muscle mass is a common consequence of rapid weight loss, immobilization, aging, and diseases such as cancer, diabetes, and heart failure. This loss impairs mobility and strength, reduces quality of life, and increases susceptibility to injury. While exercise and nutritional therapies can help preserve muscle mass during disease and promote muscle recovery during rehabilitation, these strategies are often less effective or feasible for older adults, patients with disabilities, or individuals with mobility-limiting conditions. This highlights the urgent need for pharmacological approaches to mitigate muscle loss. Our recent work demonstrates that genetic deletion of the TAS1R2 sweet-taste receptor in mouse skeletal muscles (mKO) significantly enhances mitochondrial health by increasing cellular NAD+ levels and activating Sirtuin 1 (SIRT1). Notably, mKO mice exhibit greater muscle mass than wild-type mice (mWT) and show accelerated muscle recovery following unilateral hindlimb immobilization (UHI), suggesting the potential of targeting TAS1R2 to enhance muscle restoration after disuse. In mKO skeletal muscle, baseline levels of the atrophy-associated transcription factor FoxO3a, a known SIRT1 substrate, and its downstream effector genes (MuRF1, MAFbx) were reduced, indicating that TAS1R2 signaling may converge with SIRT1-mediated pathways that regulate muscle atrophy. I hypothesize that genetic ablation of TAS1R2 increases skeletal muscle mass through SIRT1-mediated regulation of FoxO transcription factors. In Aim 1, I will investigate the interaction between TAS1R2 signaling and mechanisms governing muscle mass turnover. Using mWT, mKO, and muscle-specific TAS1R2 overexpression (mTg) mouse models and corresponding myotube cultures, I will evaluate the effects of TAS1R2 deletion and activation on the SIRT1-FoxO signaling axis and investigate the causal relationship between TAS1R2 inhibition and increased muscle mass. In Aim 2, I will explore the effects of TAS1R2 deletion on muscle mass recovery after disuse-induced atrophy. mWT and mKO mice will undergo UHI for 7 days, followed by 0–5 days of recovery, during which I will: (a) assess TAS1R2-SIRT1-FoxO signaling and key regulators of protein turnover, and (b) evaluate TAS1R2-dependent muscle mass and strength adaptations. In summary, this study aims to establish TAS1R2 as a novel therapeutic target to promote muscle growth and recovery, addressing a critical need for effective interventions to counter muscle loss associated with aging and disease.
