UC San Diego

Cerebral palsy (CP) is a heterogeneous disorder caused by an upper motor neuron lesion in the developing brain, leading to significant muscle impairments including muscle contractures, which limit range of motion around a joint. A deeper understanding of muscle adaptations in CP could lead to dramatic therapeutic improvements. The aim of this work, therefore, was to identify architectural and cellular components of muscle dysfunction in CP. Chapter 1 introduces basic muscle physiology and gives an overview of previously reported muscular changes that occur in CP. Chapter 2 presents the first simultaneous study of muscle fascicle and sarcomere length. In the soleus muscle, fascicle lengths appeared similar between patients with CP and typically developing (TD) individuals only because their sarcomeres were highly stretched. The combination of macro and microscopic data provide a clearer picture of the muscle in CP and point to reduced force production potential due to long in vivo sarcomere lengths. To determine the implications of long sarcomeres on the in vivo passive mechanical environment in CP, Chapter 3 measured passive fiber and fiber+extracellular matrix bundle stiffness in the soleus and gastrocnemius of patients with CP. At measured in vivo sarcomere lengths, both bundles and fibers appeared much stiffer in CP muscle. The similar stiffness of fibers and bundles at in vivo lengths indicated that the increase in stiffness was driven by stiffer fibers rather than by increase extracellular matrix stiffness. To probe possible culprits for fiber alterations such as long sarcomeres and increased stiffness seen in Chapters 2 and 3, Chapter 4 explored characteristics of satellite cells, muscle stem cells critical for growth and repair. These cells must be able to proliferate, move to sites of injury and growth, and differentiate to form mature fibers. Reduced CP satellite cell populations have been previously reported, so proliferation deficits were predicted. When proliferation, motility, and fusion were measured, however, no difference was seen in either proliferation or motility. Interestingly, differentiation and fusion capability was reduced in CP cells. This work paves the way for further studies into satellite cell function in CP, which could lead to completely new therapeutic directions