Project Summary
Anterior Cruciate Ligament (ACL) injury and subsequent reconstruction result in disrupted neuromuscular
pathways which have been linked to protracted quadriceps weakness and atrophy. There is a significant gap in
knowledge concerning the signaling cascades that precipitate peripheral quadriceps deficits, limiting progress
in the field to address the inceptive events underlying poor functional recovery. Lacking mechanistic evidence
hinders the development of targeted rehabilitation protocols to address quadriceps atrophy and weakness that
often persist far beyond return to activity. Pilot data in this proposal has identified a molecular signature of
quadriceps neuromuscular dysfunction that appears following the initial ACL injury and is further exacerbated
by reconstruction. Early molecular changes following ACL reconstruction culminate in local quadriceps
denervation and weakness. Additionally, provided data show this molecular signature to be responsive to
neuromuscular electrical stimulation (NMES), providing a heretofore previously unknown mechanistic target of
NMES. Conflicting results from studies lacking rigor and mechanistic insight have limited the efficacy and
utilization of NMES following ACL injury, hindering its therapeutic potential. The overarching hypothesis of this
proposal is that ACL injury results in rapid quadriceps neuromuscular remodeling and local denervation, which
results in subsequent quadriceps atrophy and weakness. Further, NMES is hypothesized to mitigate
denervation-induced molecular signaling within the quadriceps, providing critical mechanistic insight. Three
interconnected but independent aims will address the overarching hypothesis. Specifically, innovative pre-
clinical gain and loss of function experiments will establish causative roles for specific signaling cascades
within the quadriceps that are critical for responsiveness to NMES. Additionally, a rigorous and targeted clinical
trial will address gaps in knowledge surrounding NMES that have previously limited acceptance and utilization.
Results of the current study will provide necessary mechanistic insight to overcome a critical barrier in the
development of evidence-based guidelines. Results from this work will directly lead to new testable treatments
to advance the care of individuals with ACL injuries that will remedy the pervasive issue of protracted
quadriceps weakness.
