Translational Research on Novel Therapeutic approaches for Treating Skeletal muscle atrophy Kim Hyun-Jun School of Life Sciences Gwangju Institute of Science and Technology

Abstract

Skeletal muscle atrophy arises from numerous factors, including aging, hormonal imbalances, and inflammation, and contributes significantly to socioeconomic burdens. Advanced metastasis often leads to cachexia, a complex syndrome characterized by muscle wasting and responsible for approximately one-third of cancer-related deaths. Despite the severe impact of both sarcopenia and cancer cachexia, no approved drug therapies currently exist for either condition. Among potential therapeutic targets, Arachidonate 5-lipoxygenase (Alox5) has gained attention for its role in various diseases, while C-X-C motif chemokine ligand 5 (CXCL5), a pro-inflammatory cytokine secreted by cancer-associated fibroblasts (CAFs), has been implicated in cancer progression and immune cell recruitment. However, the roles of Alox5 inhibition in sarcopenia and CXCL5 neutralization in cancer cachexia have not been fully explored. This study focused on investigating the potential of Alox5 inhibition and CXCL5 neutralization as therapeutic strategies for muscle atrophy. Using cell-based models, animal studies, and human skeletal muscle primary cells, we evaluated the effects of Alox5 inhibition in sarcopenia and CXCL5 neutralization in cancer cachexia. Malotilate, a clinically approved drug with Alox5-inhibitory properties, was identified as a candidate for repurposing. The mechanisms of action were assessed by evaluating the expression of key regulatory pathways involved in muscle atrophy, with gene knockdown and RNA sequencing confirming the effects. In sarcopenia models, Alox5 inhibition via malotilate treatment showed significant protective effects against muscle wasting. Myotubes treated with dexamethasone or conditioned media (CM) exhibited a marked reduction in catabolic responses when treated with malotilate. Similarly, Alox5 gene knockdown in these models provided anti-atrophy benefits without affecting the myogenic differentiation process. In vivo 김현준Hyun-Jun Kim ( ), Translational Research on Novel Therapeutic approaches for Treating Skeletal muscle atrophy 근감소증 치료를 위한 신규 치료제에 대한 중개연구( ), School of Life Sciences, 130p, Prof. Darren Williams PhD/LS 20184016 studies demonstrated that Alox5 inhibition preserved muscle mass, increased muscle fiber cross-sectional area, and improved muscle force/strength, while downregulating atrogene expression. In aging models of sarcopenia, malotilate preserved fast-twitch muscle fibers, further emphasizing the potential of Alox5 inhibition as a treatment for sarcopenia. In contrast, for cancer cachexia, CXCL5 neutralization emerged as a promising strategy. Neutralizing CXCL5 effectively inhibited cachexia in mice co-injected with HCT 116 colon cancer cells and CAFs. The suppression of CXCL5 triggered hypertrophy-related PI3K-AKT-MyoG signaling pathways and facilitated the remodeling of the muscle extracellular matrix. CAFs were identified as the primary source of CXCL5 in patient-derived tumor samples strongly associated with cachexia. Importantly, these effects were specific to the atrophy condition induced by cancer and were not observed in normal skeletal muscle. Furthermore, pharmacological targeting of Alox5 provided protection against muscle atrophy in human myotubes, reinforcing its potential application beyond cancer cachexia. These findings highlight distinct yet complementary therapeutic avenues: Alox5 inhibition shows promise for treating sarcopenia by protecting against muscle wasting and preserving muscle function, while CXCL5 neutralization offers a novel strategy for combating cancer cachexia by targeting pro-inflammatory cytokines within the tumor microenvironment. Together, these approaches provide a foundation for developing effective treatments for muscle atrophy across different pathological conditions.