UC San Diego

Cerebral palsy is an upper motor neuron lesion to the developing brain that results in motor impairments. Despite best clinical practices muscle often secondarily develops the pathologic state of contracture, where muscle stiffness limits the functional range of motion. This work aims to elucidate the mechanism of contracture in children with cerebral palsy.

Chapter 2 presents the first transcriptional study of muscle in cerebral palsy performed on both effected wrist flexors and their antagonist extensors. Results show that muscle in contracture is fundamentally different than control muscle, or other muscle pathologies. Many transcripts related to calcium handling were altered in cerebral palsy, the first such evidence of disruption within contracture. Immature transcripts were present in the muscle suggesting regeneration. This was accompanied by large increases in extracellular matrix transcription. Muscle signaling was confounding with signals of muscle growth and growth inhibition.

To better understand the relationship between gene products Chapter 3 provides a network of proteins specifically related to skeletal muscle function. The functions described include: neuromuscular junction, excitation contraction coupling, muscle contraction, cytoskeleton, extracellular matrix, energy metabolism, inflammation, and muscle hypertrophy and atrophy. These functional networks were created to provide networks specific to muscle for high throughput analysis.

These networks are applied in Chapter 4 to a more comprehensive microarray study on muscle contracture in hamstrings of patients with cerebral palsy. Again muscle in cerebral palsy was distinct from controls and there were many signs of immature muscle. However the fiber type shift was from fast-to-slow, opposite of that seen in chapter 2. A critical consistency was the large increase in extracellular matrix transcripts further implicating fibrosis.

To study the effects of this fibrosis the mechanics of single fibers were compared to that of fiber bundles and their constituent extracellular matrix. Although fiber stiffness was not changed in cerebral palsy an increase in bundle stiffness points to a functional consequence of increased extracellular matrix. This tissue stiffening is exacerbated by evidence of increased in vivo strain imposed on muscle in cerebral palsy. These studies provide the basis for future research into muscle contracture and targets for novel therapeutics.