Author(s): NGUYEN, T.1, KIM, Y.1, JO, Y.2,3, KIM, B.4, OH, C.1, RYU, D.1, Institution: GWANGJU INSTITUTE OF SCIENCE AND TECHNOLOGY, Country: KOREA, SOUTH, Abstract-ID: 1853

INTRODUCTION:
Skeletal muscle acts as an endocrine organ by secreting myokines that coordinate systemic homeostasis. While factors like irisin promote muscle health, others such as myostatin act as negative regulators. The age-related decline in beneficial age-sensitive myokines is a primary driver of sarcopenia. We hypothesized that restoring a previously uncharacterized humoral myokine could preserve muscle mass and functional integrity during aging.
METHODS:
Age-associated secreted genes were screened from GTEx skeletal muscle transcriptomes and validated via Olink plasma proteomics in elderly cohorts. Candidates were prioritized based on differential abundance and Spearman correlations with muscle function (e.g., SPPB score) using XGBoost and SHAP analysis. The lead candidate, AMPEX, was produced in CHO cells. In vitro effects were assessed in C2C12 myotubes via SUnSET protein synthesis assay. For in vivo validation, 19-month-old mice received daily AMPEX injections (0.3 nmol/kg) for 14 weeks. Phenotyping included DEXA-based body composition, muscle mass, myofiber CSA, and functional tests (treadmill and hang test), alongside toxicity analysis.
RESULTS:
Among age-associated secreted candidates, AMPEX was significantly reduced in plasma from individuals with sarcopenia compared with individuals without sarcopenia. AMPEX levels demonstrated significant positive correlations with 6-minute walk distance, grip strength, and SPPB score. In XGBoost classification models, AMPEX ranked among the top contributors for discriminating sarcopenia status, and SHAP analysis confirmed a strong and directionally consistent impact on model prediction.
In vitro, recombinant AMPEX significantly increased C2C12 myotube diameter and enhanced global protein synthesis. In vivo, 14-week administration of AMPEX in 19-month-old mice effectively attenuated age-associated muscle wasting. DEXA-based body composition analysis revealed a 10–12% increase in lean mass and a 10–15% reduction in relative fat mass compared with vehicle-treated aged controls. This was further supported by increased mass of hindlimb muscles and enlarged myofiber CSA. Functional performance was markedly enhanced; compared to the vehicle group, AMPEX-treated mice exhibited a nearly 2-fold increase in hang test duration and an approximately 1.8-fold greater treadmill running distance. Importantly, chronic daily administration induced no abnormalities in blood biochemistry or histopathological evidence of toxicity in major organs

CONCLUSION:
AMPEX is a novel age-declining myokine that links human muscle aging to functional decline. Restoration of AMPEX confers anabolic remodeling and functional resilience in aged skeletal muscle, attenuating age-associated muscle loss and performance impairment without detectable toxicity. These findings establish AMPEX as a mechanistically validated and translationally actionable therapeutic candidate for sarcopenia and age-related functional deterioration.