Sex-based Muscular Adaptations, Capillary dysfunction and functional decline impact Knee-related psychosocial outcomes after acute knee injury (SMACK)

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Abstract Following an Anterior Cruciate Ligament (ACL) reconstruction, females have worse outcomes; however, skeletal muscle biology and function have preferentially been studied in males. These observations suggest that there are sex-based differences in the biological mechanisms contributing to recovery of muscle function. Intriguing pilot data in this proposal show preferential impairment in the recovery of quadriceps muscle and function and diminished psychosocial recovery in females as compared to males following ACL reconstruction. This proposal seeks to test the novel hypothesis that following an ACL injury, females experience exaggerated muscle cellular and molecular deficits, hindering their recovery of strength, resulting in pronounced deficiencies in gait mechanics and disproportionally worse psychosocial recovery compared to males. By identifying the cellular and molecular foundation of sex-based differences, subsequent clinical trials can test sex specific approaches to improve outcomes for women after ACL injury. We will in Aim 1 define the molecular, cellular and morphological sex-based differences in quadriceps muscle after ACL injury and reconstruction. In Aim 2 determine the effect of sex on knee function after an ACL reconstruction. Lastly, in Aim 3 will determine the timing and magnitude of psychosocial recovery differences between females and males following an ACL reconstruction. Results from this work will exert an immediate impact on clinical practice guidelines, as well as identify critical therapeutic targets needed to propel subsequent evidence-based clinical trials designed to improve rehabilitative outcomes for females.