Role of muscle stem cells in sarcomere addition and contractures

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Project Summary Cerebral Palsy (CP) affects more than 750,000 children and adults, who show impaired muscle growth and develop muscular contractures that limit their joint range of motion. Muscles fibers are composed of their basic contractile proteins, sarcomeres arranged in series (longitudinally) and in parallel (cross-sectionally) and sarcomere length is associated with force production. During postnatal development muscles grow in length by increasing their serial sarcomere number, in order to maintain optimal sarcomere lengths. Muscles maintain this ability throughout life, such that maintaining a muscle in a stretched position leads to an increase in sarcomere number while maintaining it in a shortened position leads to loss of sarcomeres. Contractures have decreased numbers of sarcomeres-in-series and overstretched sarcomere lengths, suggesting reduced ability for muscular growth/adaptation by serial sarcomere addition. Muscle stem cells, i.e. satellite cells are required for postnatal muscle growth, repair and regeneration. Their pool size is associated with myogenic potential and contractured muscles show a significantly reduced number. Endurance training has been shown in animal and human studies to significantly increase the number of muscle stem cells. Thus, the objective of this proposal is to utilize a muscle stem cell-specific transgenic mouse model (Pax7CreER/+;Rosa26DTA/+) that can undergo conditional knockdown to evaluate if adequate muscle stem cell number is required for sarcomere addition, recovery from contractures and whether endurance exercise can facilitate recovery. The first aim will test our primary hypothesis that a full cohort of muscle stem cells are required for adequate sarcomere addition and recovery from contractures. We predict that in the presence of a reduced muscle stem cell number sarcomere addition is limited, and hampers recovery from contractures. In addition, serial sarcomere number, rather than change in extracellular matrix will explain residual contracture severity. The second complementary aim will test our secondary hypothesis that active rehabilitative strategies will increase muscle stem cell number and facilitate recovery from contractures by sarcomere addition. We predict that endurance training will facilitate recovery from contractures more than serial casting or cage remobilization by increased sarcomere addition secondary to an increase in muscle stem cell number. The results of this proposal could potentially lead to therapies for prevention and treatment of contractures, a clinically vexing problem that cause significant disability in children with CP as well as in millions of individuals with stroke, multiple sclerosis and spinal cord injury.