Late-life oral supplementation with apigenin mitigates loss of skeletal muscle strength and mass, exercise intolerance, and frailty with aging in mice

Abstract

Sarcopenia is a skeletal muscle disease that often manifests with aging, characterized in part by low skeletal muscle strength and mass as well as low physical performance (i.e., exercise intolerance) compared to young adults, which contributes to increased frailty. There remains a need to develop novel and adherable interventions for mitigating these losses with aging. Increased flavonoid consumption is inversely related to frailty in mid-life/older adults. Late-life oral supplementation with the natural flavonoid apigenin can improve select age-related conditions; however, its effect on treating features of sarcopenia is unkown. Hypothesis. We hypothesized that late-life oral supplementation with apigenin would result in greater grip strength and skeletal muscle mass, increased exercise tolerance, and lower frailty with aging. Methods. Young (Y; 6 mo) and old (O; 27 mo) male C57BL/6N mice consumed drinking water containing vehicle (control [C]; 0.2% carboxymethylcellulose; YC, n=10; OC, n=7) or apigenin (Api; 0.5 mg/mL in vehicle; Y-Api, n=10; O-Api, n=9]) for 6 weeks. Skeletal muscle strength was measured by forelimb grip strength. Skeletal muscle mass was assessed as quadriceps weight relative to body mass. Exercise tolerance was determined using a rota-rod and quantified as time spent running while the rota-rod accelerated from 50-100% of maximal running speed. Frailty was evaluated using a validated frailty index. Exercise tolerance was assessed before and after the intervention, and skeletal muscle strength, mass, and frailty were quantified at the end of the intervention. Data are reported as mean±SEM. Results. Forelimb grip strength. Forelimb grip strength (g of force/bodyweight) was higher in YC vs. OC (6.7±0.3 vs 5.3±0.2, P=0.001) and in O-Api (6.1±0.2, P=0.006 vs OC). However, O-Api was still lower than Y-Api (YApi, 6.9±0.3, P=0.025 vs O-Api). There were no differences between Y-Api and YC (P=0.520). Quadriceps mass. Quadriceps mass (mg/bodyweight) was higher in YC vs OC (9.5±0.6 vs 7.8±0.4, P=0.051), in O-Api vs OC (O-Api, 9.9±0.6; P=0.005 vs OC), and in Y-Api vs YC (11.1±0.5, P =0.064 vs YC). O-Api was not different than Y-Api (P=0.111). Exercise tolerance. Prior to the intervention we observed differences with aging (YC, 1233±141 sec vs OC, 614±128 sec; P=0.010), but no differences between treatment groups (YC vs Y-Api, P=0.115; OC vs O-Api,P=0.177). Following the intervention, exercise tolerance was increased in the O-Api group (pre: 443±50 sec vs post: 1118±113 sec, P<0.001) but unchanged in other groups (P=0.137-0.543). Frailty. Frailty index was higher in OC vs YC (0.24±0.02 vs 0.02±0.01, P<0.001). Frailty in O-Api mice was higher than Y-Api (0.18±0.01 vs 0.02±0.01 P<0.001), but lower than OC (P=0.005). There were no differences between Conclusions. Oral supplementation with apigenin may be an effective therapeutic strategy to treat select characteristics of sarcopenia and associated frailty with aging.

NIH AG055822-02S1, K99 HL159241, H2020-MSCA-IF-2019: 892267, T32 DK007135