(771.8) Inhibition of YAP signaling improves recovery in injured skeletal muscle

Poster Board Number: E614

Shama Iyer (University of Maryland School of Medicine), Sameer Shah (University of California San Diego), Christopher Ward (University of Maryland School of Medicine), Joseph Stains (University of Maryland School of Medicine), Eric Folker (Boston College), Richard Lovering (University of Maryland School of Medicine)

Skeletal muscle experiences mechanical forces that regulate its development, hypertrophy, and homeostasis. YAP (Yes-associated protein) not only serves as an indicator of nuclear mechanical signals, but can also induce a wide range of downstream signaling cascades. We previously reported increased YAP signaling in healthy (wild type, WT) muscle following isometric contractile loading, and constitutively active YAP signaling in the muscles of mdx mice (dystrophin-null, murine model of Duchenne muscular dystrophy, or DMD) and aged mice. We tested the hypothesis that increased YAP signaling contributes to the loss of muscle function following eccentric contraction-induced injury in WT muscle. We also tested the hypothesis that pharmacological inhibition of YAP signaling (verteporfin, 100 mg/kg delivered via intraperitoneal injection every other day immediately following injury for 10 days) improves muscle function following injury. We found increased YAP signaling following eccentric contraction-induced muscle injury in healthy muscles, indicated by increased gene expression of YAP and its downstream targets. Moreover, pharmacological inhibition of YAP activity resulted in hastened recovery following eccentric contraction injury. Following 50 eccentric contractions to the quadriceps muscles, vehicle (DMSO) treated muscles had a loss of force of 44.8 ± 14.1% and 42.9 ± 17.1% at days 2 and 4 following injury, while verteporfin treated muscles had a loss of force of 13.7 ± 24.7% and 9.05 ± 24.5% at days 2 and 4 following injury. Both groups were fully recovered at 6 days following injury. We conclude that reducing YAP signaling improves muscle function following injury to WT muscle, and could play a significant role in ameliorating muscle pathology in dystrophic and aged muscle.

This work was supported by grants to RML from the University of Maryland Claude D. Pepper Older Americans Independence Center (UM-OAIC) and the National Institutes of Health (R56AR073193), to SRI from the National Institutes of Health (K01AR074048) and the Muscular Dystrophy Association development grant (MDA 577897).