PRISMS: Pervasive Role of Incretin-mimetics on Skeletal Muscle homeostasis during Sarcopenic obesity

• Applicant: Dr. Aniket Sunil Joshi, Ph.D.
• Subject Area: Anatomy and Physiology ; Biogerontology and Geriatric Medicine
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 580751061

According to the WHO, over 50% of the world’s population is overweight or obese. Incretin mimetics, including the GLP-1 receptor agonist semaglutide (Ozempic/Wegovy) and emerging polyagonists (e.g., retatrutide), are promising anti-obesity agents. While these therapies effectively reduce fat mass in obese adults, some clinical trials suggest a disproportionate loss of lean body mass, which is primarily comprised of skeletal muscle tissue. In addition, discontinuation of incretin-based therapy leads to regain of lost body weight, often coupled with adverse cardiometabolic effects. Intriguingly, most clinical and pre-clinical studies to date have focused on middle-aged populations, leaving a critical knowledge gap regarding effects in aged subjects, who represent a significant proportion of those with obesity. Using a mouse model of diet-induced obesity, this project aims to elucidate whether incretin mimetics have a more pronounced effect on skeletal muscle mass and function in aged obese mice compared to younger counterparts (Objective 1). We will also assess how treatment cessation and weight cycling affect muscle integrity (Objective 2). To further elucidate the role of incretin mimetics on maintenance of muscle mass, we will examine whether incretin mimetics exacerbate cast immobilization-induced muscle atrophy (Objective 3) and delay muscle recovery after cast removal (Objective 4) in adult and aged obese mice. Additionally, the proposed study will also investigate the effects of incretin mimetics on primary human and mouse muscle cells during and after differentiation, and determine whether the species-specific abundance of GLP-1 receptor leads to different outcomes. Collectively, our study will provide insights into the safety and efficacy of incretin mimetics in the context of sarcopenic obesity, and may inspire clinical investigations that result in adjusted guidelines.

• DFG Programme: Position