Project R-16558

A secret woven into the matrix: decoding the mechanisms of persistent muscle weakness upon ACL reconstruction and the regenerative potential of ketone ester. (Research)

Anterior cruciate ligament (ACL) injuries are among the most common orthopedic injuries and quickly induce muscular weakness. Of primary concern, this muscular deficit is unresponsive to rehabilitation training, resulting in muscular weakness for up to 8 years following ACL reconstruction (ACLR). While it is clear that this is driven by intrinsic muscle weakness, the underlying biomolecular changes remain unclear, hindering the development of effective countermeasures. Therefore, our first aim is to unveil the biomolecular changes driving muscle weakness post-ACLR. Our recent discoveries point to the extracellular matrix (ECM) of skeletal muscle as a key factor in the (in)ability to reverse muscle weakness. Therefore, we will leverage specialized techniques that are only available in a select few laboratories to generate a comprehensive characterization of skeletal muscle ECM dynamics following ACLR. Additionally, we recently identified ketone ester (KE) ingestion as a novel strategy to improve muscular rehabilitation following simple disuse, which at least partly occurred through ECM changes. Thus, our second aim is to assess if KE can improve muscle function and clinical outcomes following ACLR. Finally, our most recent data showed that the circulating milieu upon KE ingestion directly improves ECM function. Therefore, our third aim is to identify the blood factors mediating this effect and provide proof of concept of their potential to enhance human muscle function.

01 October 2026 - 30 September 2030