Translational Research on Novel Target Discovery and Therapeutic Development for Age-related Sarcopenia

Abstract

Skeletal muscle wasting, including sarcopenia and drug-induced atrophy, represents a significant clin ical challenge that impairs mobility and increases mortality in the elderly and chronically ill. Despite the growing socio-economic burden, no FDA-approved pharmacological therapies currently exist. This dissertation explores translational strategies to counteract muscle wasting by identifying novel signalin g regulators and developing bioactive compounds. First, I investigated Dual-specificity phosphatase 22 (DUSP22) as a critical mediator of muscle atro phy. DUSP22 expression was significantly upregulated in sarcopenia patients and various murine mo dels of muscle wasting, including aging, immobilization, and dexamethasone (Dex) treatment. Overex pression of DUSP22 disrupted myogenesis and activated the expression of key atrogenes, such as atr ogin-1 and MuRF-1. Conversely, DUSP22 knockdown or pharmacological inhibition using the small molecule BML-260 successfully prevented muscle wasting across multiple models. Mechanistically, ta rgeting DUSP22 suppressed the JNK-FOXO3a signaling axis, a master regulator of muscle protein d egradation. Notably, this therapeutic effect occurred independently of Akt activation, suggesting a no vel pathway to inhibit muscle wasting without interfering with Akt-mediated proteostasis. Second, I characterized Gymnemantoside A (GmA), a novel bioactive triterpenoid isolated from the medicinal plant Gymnema inodorum through bioactivity-guided screening. GmA was found to amelior ate steroid-induced skeletal muscle atrophy by bridging the connection between glucocorticoid (GR) a nd insulin receptor (IR) signaling. Molecular docking and surface plasmon resonance (SPR) assays c PhD/LS 20204093 Sang-Hoon Lee (이상훈), Translational Research on Novel Target Discovery an d Therapeutic Development for Age-related Sarcopenia (노인성 근감소증의 신규 치료 타겟 발굴 및 치료제 개발을 위한 중개 연 구), Department of Life Sciences, College of Life Sciences and Medical Engine ering. 2026. 134p, Prof. Darren Williams onfirmed that GmA directly interacts with the IR tyrosine kinase domain, promoting its activation ev en under conditions of glucocorticoid stress. Treatment with GmA successfully recovered myotube di ameter and muscle fiber cross-sectional area (CSA) by activating the Akt/mTOR pathway, which in t urn downregulated atrogene expression and normalized dysregulated autophagy. Furthermore, GmA tr eatment significantly increased the proportion of fast-twitch Type IIb myofibres, which are predomina ntly lost during the progression of sarcopenia. Finally, I explored a new regulatory mechanism for muscle differentiation involving Adcy10. My re search demonstrated that the inhibition of Adcy10 suppresses the OAS (2'-5' oligoadenylate synthetas e) pathway, subsequently reducing the activation of RNase L. This specific reduction in RNase L ac tivity was shown to promote myogenic differentiation, identifying the Adcy10-OAS-RNase L axis as a potential target for enhancing muscle regeneration and repair. In conclusion, this dissertation provides a comprehensive translational framework for treating skeleta l muscle wasting. By delineating the DUSP22-JNK-FOXO3a axis, characterizing the multi-target effic acy of GmA, and identifying the Adcy10-mediated differentiation pathway, these findings offer promi sing therapeutic candidates and strategies for future clinical applications in muscle-related degenerativ e disorders.