An in vitro model to replace animal testing of muscle physiology and function

Skeletal muscles are the motors that drive our movement, posture and breathing making them essential to life. The loss of skeletal muscle function in the elderly and as a result of chronic disease is a major cause of falls and decreases quality of life and lifespan. Skeletal muscle also plays an essential function in metabolism. Loss of muscle metabolic function can cause and/or exacerbate a number of chronic diseases, including heart disease, high blood pressure, obesity, diabetes, cancer, depression, and osteoporosis. As a result, a lot of time and money is invested in studying skeletal muscle. Beyond the human investment, every year over 500,000 animals are used to study how the physiology and function of muscle adapts to disease, genes, exercise, and drugs. Therefore, creating an alternative method for the study of muscle physiology and function could not only reduce the number of animals used for this purpose but could improve the quality and length of human lives as well. We have recently engineered a model of a muscle that has the potential to achieve this. In order to further develop our model and test its usefulness as a replacement for animal studies, this proposal looks to: i) engineer muscle from immortal cells so that animal donors are no longer required; ii) create an interface between our engineered muscle and our experimental machines; iii) create new machines that would allow us to better mimic exercise and growth and that could be developed commercially so that others could do similar experiments at a reasonable cost; and iv) compare whether the response to simulated exercise in engineered muscles is similar to the response of an animal to exercise.

Skeletal muscle provides mechanical power for locomotion, posture and breathing, making it essential to life. The loss of skeletal muscle function in elderly populations and in patients with chronic diseases is a major cause of falls, morbidity and mortality. Beyond these vital functions, skeletal muscle also plays an essential role in the regulation of whole body metabolism. Loss of metabolic function leads to and/or exacerbates a number of chronic diseases, including coronary heart disease, hypertension, obesity, type 2 diabetes, cancer, depression, osteoporosis, and sarcopenia. As a result, skeletal muscle is the focus of intense scientific investigation. Every year over 500,000 animals are used to study how the physiology and function of muscle adapts to disease, genetic alteration, altered loading, and pharmacological agents. Creating an in vitro alternative for the study of muscle physiology and function could not only reduce the number of animals used for this purpose, but could provide unique data since the in vitro environment provides complete control over the milieu of the tissue. We have recently engineered a model of a muscle that has the potential to achieve this. In order to further develop our model and test its usefulness as a replacement for animal studies, this proposal looks to: i) rapidly engineer muscle from immortalized cell lines that could be genetically modified so that gene function could be tested in vitro; ii) create a mature muscle machine interface that would decrease the impedance mismatch and prevent failure at the tissue anchors; iii) create new bioreactors that would mimic muscle physiological function, allow high throughput screening and could be developed commercially at a reasonable cost; and iv) compare the physiological and functional response to resistance and endurance exercise in experimental animals to engineered tissues stimulated within the next generation of functional bioreactors.