R03 awarded to develop tools for controlling rotator cuff muscle activation using light

The Killian Lab recently received funding from the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development) to develop in vivo optogenetics tools for the control of skeletal muscle contraction. We will use these tools to identify the role that increased muscle loading plays on enthesis maturation during postnatal growth, as well as to study how adaptation and healing are influenced by increased muscle loading following rotator cuff injury. This work is in collaboration with C. Savio Chan, PhD (Northwestern University) and Matthew Hudson, PhD (University of Delaware; KAAP).

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Channelrhodopsin-2 (hChR2), fused with YFP, can be localized in skeletal muscle using tissue-specific cre-mediated recombination.

Project summary: Rotator cuff health relies on the functional attachment of cuff muscle and tendon to bone via the tendon- bone enthesis. The enthesis transmits muscle forces to the skeleton, and the structure and function of the enthesis is dependent on muscle loading. In the case of muscle or nerve injury at birth, the enthesis fails to properly form due to traction-induced muscle disuse of the shoulder at childbirth. Return of muscle function during muscle recovery in adolescents can predispose the enthesis to damage and rupture due to delayed enthesis formation during critical periods of postnatal maturation. We have recently shown the requirement for muscle loading during the growth and maturation of the enthesis, as well as for proper healing of the repaired rotator cuff.

While it is understood that the muscle loading is required for the development of the enthesis, experimental approaches that induce controlled muscle activity during growth are non-existent. One potential way of controlling muscle activation is via the use of optogenetic tools, which control cell behavior via light-activation. The Killian Lab is focused on identifying interventions, such as regulating muscle force, that promote the maturation and remodeling of the enthesis. This work will have implications for treating developmental disorders like muscle disuse, as we will develop approaches for understanding how muscle activation influences the maturation of the enthesis as well as how the adolescent enthesis adapts following muscle disuse and return to loading. Using transgenic in vivo models and cre-recombination, we will develop and validate a skeletal muscle-specific expression of channelrhodopsin-2 (hChR2)/YFP fusion protein for the activation of skeletal muscle following exposure to blue light (450-490nm).

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