Frailty impairs skeletal muscle resilience to downhill running stress in aged female mice

Frailty is a clinical syndrome marked by diminished physiological reserve and function. While skeletal muscle dysfunction is central to frailty, most preclinical models focus on basal function and overlook responses to physiological stress. Here, we examined the impact of frailty on skeletal muscle resistance and resilience to stress using a physiologically relevant model of downhill running stress. Female C57BL/6 mice (n=47; >17 months) were stratified into frail or robust groups by phenotyping and further randomized to undergo two bouts of downhill running or remain cage sedentary. Twenty-four hours later, contractile function was assessed ex vivo in the extensor digitorum longus (EDL) and soleus muscles. RNA was extracted from the gastrocnemius of randomly selected samples and analyzed by RNA sequencing. Despite comparable specific tetanic force, frail mice exhibited greater fatiguability and impaired recovery kinetics in the EDL following running stress. RNA sequencing revealed divergent transcriptional signatures in robust and frail mice in response to running, including upregulation of mitochondrial bioenergetic and complex assembly pathways in robust mice and downregulation in frail mice. These data demonstrate that the stress of downhill running unmasks latent impairments in the skeletal muscle of frail mice, and that mitochondrial dysfunction and/or redox imbalance may be potential contributors to reduced muscle resilience. Overall, our results highlight the importance of incorporating physiological stress paradigms to uncover frailty-associated muscle impairments and suggest that dynamic measures of stress responses may serve as more sensitive functional indicators of frailty than baseline muscle properties alone.