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

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.