(PTFS15-02-24) Effects of Coumarin-Type Compounds on Diabetes-Associated and Age-Related Sarcopenia

Objectives: Sarcopenia is a musculoskeletal disease characterized by loss of muscle mass and function. This study aimed to investigate the mechanism(s) involved in sarcopenia associated with type 2 diabetes and aging under in vitro and in vivo conditions. Additionally, the study examined whether coumarin-type compounds including fraxetin and aesculetin, alleviated sarcopenia induced by type 2 diabetes and aging.

Methods: For in vitro sarcopenia models, human primary skeletal muscle cells (SkMCs) were exposed to 33 mM high glucose and 100 μg/ml advanced glycation end products (AGE) with and without 10 μM fraxetin and aesculetin. For in vivo sarcopenia models, db/db mice and senescence accelerated mouse-prone (SAMP)-8 mice were introduced for type 2 diabetes and aging, respectively. As respective control mice, db/m and senescence-accelerated mouse resistant (SAMR)-1 were employed. These animals were orally treated with 10 mg/kg fraxetin and aesculetin for 10-12 weeks.

Results: When SkMCs were treated with high glucose or AGE for 7 days, no cytotoxic damage was observed. Muscle atrophy biomarkers of MAFbx and MuRF1, were induced by AGE in 3-5 days, which was diminished by treating 10 μM fraxetin and aesculetin to SkMCs. Oral administration of 10 mg/kg fraxetin and aesculetin did not restore muscle mass in diabetic mice, as evidenced by weighing skeletal muscles of legs and scanning of dual energy x-ray absorptiometry (DEXA). However, these compounds slightly lowered fasting glucose and glycated hemoglobin (HbA1c) levels. On the other hand, the DEXA scanning showed that lean body mass was restored in SAMP8 mice supplemented with 10 mg/kg aesculetin. Therefore, these results suggest that aesculetin attenuated aging-related sarcopenia but not diabetic sarcopenia.

Conclusions: Coumarin-type compounds, especially aesculetin, may be promising agents to alleviate the loss of skeletal muscle mass induced by age-related sarcopenia.

Funding Sources: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (2021R1A6A1A03044501 and 2022R1A2B5B01001861).