ABSTRACT
The rotator cuff is composed of 4 muscles that stabilize the shoulder and controls upper arm range of motion. Tears in the
tendons of these muscles, known as rotator cuff tears (RCTs), are among the most common debilitating shoulder injuries.
While RCTs can be surgically repaired, the rate of retear is significant and has been correlated to high levels of rotator cuff
muscle fatty infiltration and fibrosis. The precise source of this intramuscular fat and fibrosis is unclear; however, a
heterogeneous population of muscle resident non-myogenic mesenchymal cells, known as fibroadipogenic progenitors
(FAPs), have been implicated in many skeletal muscle pathologies, particularly those in which intramuscular fat and fibrosis
are abundant—as seen in RCTs. We and others have recently demonstrated in mice that PDGFRa-expressing FAPs expand
following massive RCTs and likely contribute to the accumulation of intramuscular fat and fibrosis that accompanies rotator
cuff muscle atrophy. While these findings are important, virtually nothing is known regarding the molecular signals associated
with the promotion of FAP differentiation into fibrogenic and adipogenic fates, nor the factors that may be secreted by FAPs
to drive rotator cuff muscle atrophy following RCT. Utilizing murine models of massive RCTs, genetic lineage tracing/reporter
analysis, ex vivo functional testing, as well as sophisticated bulk RNA-sequencing assays from isolated FAPs and muscle
fibers, we will define the precise tissue, cellular, and molecular changes associated with the rotator cuff muscle pathology
following RCTs (Aim 1). Further, it remains unknown if the novel FAP subpopulations discovered by our lab in lower limb
muscles exist within the rotator cuff musculature, or whether these specific FAP subpopulations change following RCT. Using
murine models of massive RCTs, genetic reporter analysis, sophisticated single cell RNA-sequencing assays, and lightsheet
microscopy, we will identify FAP heterogeneity within rotator cuff muscles following massive RCTs (Aim 2). These Aims will
ultimately address my overarching hypothesis that FAPs or FAP subpopulations are critical regulators of the rotator cuff
muscle pathology following massive RCT, which involves specific cytokines, adipokines, and other signaling molecules that
promote adipogenesis, fibrogenesis, and muscle atrophy, and prevent regeneration. This work will provide vital information
to our understanding of the cellular and molecular roles for FAPs in RCT induced fatty infiltration, fibrosis, and the muscle
atrophy associated with RCTs.
