Novel Therapy for Sarcopenia

Novel Therapy for Sarcopenia Abstract Sarcopenia, characterized by loss of skeletal muscle mass, quality, and strength, is a common hallmark of ageing affecting 5-13% of 60-70 year-old individuals, increasing to 11-50% of those aged 80 and above (von Haehling, 2010). Obese and diabetic patients are at increased risk as these conditions greatly aggravate the metabolic disturbance underlying the muscle wasting (Arnold, 2024). Preclinical and clinical studies have shown differential impacts of anti-diabetic drugs on skeletal muscle mass, strength, and performance. The meta- analysis of Ida et al. (2021) [18 randomized controlled trials (1,363 subjects)] found that the fat-free mass (FFM) [as an alternative index of muscle mass], was significantly reduced by semaglutide, dapagliflozin, and canagliflozin when compared to metformin or placebo. Thus, not unexpectedly, the recent enthusiastic and widespread acceptance of GLP-1-based therapies for obesity has witnessed a major uptick in therapy-induced sarcopenia: weight reduction affects both adipose as well as muscle tissue (Zhang, 2021; Arnold, 2024). Our proposed therapy, based on a novel adipokine, isthmin 1 (Ism1), addresses the pathogenesis of these metabolic syndromes while preserving muscle function. Ism1 plays a crucial role in the modulation of glucose uptake in both adipocytes and muscle cells. Ism1 promotes protein synthesis in muscle, executing this critical function by activating the PI3K/AKT/S6 pathway while suppressing protein degradation pathways. This regulation of proteostasis prevents and reverses age-related cellular changes, including sarcopenia/muscle atrophy. Presently, the short half-life (minutes) of Ism1 limits its clinical application. To address this issue, we will generate a panel of longer lived versions, rank order their activity in vitro followed by proof-of-concept studies in a rodent model of sarcopenic obesity. We anticipate that the outcome of this work will generate a muscle- sparing therapy for age-related sarcopenia as well as the sarcopenia that complicates diabetes and obesity. However, for efficient commercialization and clinical development, we will initially focus our efforts on sarcopenic obesity.