Abstract
Glial cell line-derived neurotrophic factor family receptor α-like (GFRAL) is the exclusive receptor for growth differentiation factor 15 (GDF15) and plays distinct roles in various diseases. However, its impact on sarcopenia remains poorly understood. This study, including White British and Chinese participants, demonstrated that elevated serum levels of GDF15 and its receptor GFRAL are associated with an increased risk of sarcopenia, particularly among individuals with low physical performance. While GDF15 exerts effects across the whole population, GFRAL appears to be more detrimental in women. Complementary single-cell RNA sequencing and immunohistochemical analyses in animal models further support the involvement of the GDF15-GFRAL axis in mediating skeletal muscle damage. These findings highlight the clinical and preventive relevance of the GDF15-GFRAL axis and underscore the need for future mechanistic studies to elucidate its role in sarcopenia.