Joint contractures that occur after head injury, stroke, spinal cord injury and cerebral palsy (CP) have devastating functional consequences. Contractures represent a vexing obstacle to the rehabilitation process and many times the only treatment for contracture is surgical tendon transfer or release, both of which are highly invasive and do not necessarily restore muscle function. The purpose of this proposal is to understand the changes that occur in muscles after contracture formation and to test conservative treatment options. The specific upper motor neuron lesion (UMN) population to be studied is children with cerebral palsy (CP). This is due to the large number of children with CP seen in the rehabilitation setting and the number who undergo surgical correction for contracture (making their muscle tissue available). Biomechanical and structural properties of muscle from patients with contractures will be measured in vitro after surgery to determine the basis for the changes in passive mechanical properties. Then, a complete gene expression profile will be generated on these tissues to determine how the physiological pathways activated explain the functional results obtained.
The specific aims of this proposal are: (1) to define the biological and biomechanical properties of muscles from children with CP and to contrast and compare these properties with age- and muscle-matched normal tissue, age- and muscle- matched atrophic tissue, (2) To determine the extent to which muscle and/or connective tissue properties are accurately reflected by the clinical exam, and (3) To measure the biological response of human semitendinosus muscles compared to age- and muscle-matched normal tissue, and age- and muscle-matched atrophied tissue. This proposal is based on preliminary obtained from actual human muscles after contracture due to upper motor neuron lesion. In addition to increasing our understanding of muscle after contracture, these experiments may lead to novel, nonsurgical interventions to treat skeletal muscle contractures.

Public Health Relevance

Skeletal muscle contractures that occur after head injury, stroke, spinal cord injury, multiple sclerosis and cerebral palsy are devastating. They limit function of the arms and legs, can prevent hygiene and can cause extreme pain. The purpose of this application is to study how contractures form and to develop nonsurgical methods to treat them.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057393-05
Application #
8695085
Study Section
Musculoskeletal Rehabilitation Sciences Study Section (MRS)
Program Officer
Nuckolls, Glen H
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$327,046
Indirect Cost
$115,366
Name
University of California San Diego
Department
Orthopedics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Mathewson, Margie A; Lieber, Richard L (2015) Pathophysiology of muscle contractures in cerebral palsy. Phys Med Rehabil Clin N Am 26:57-67
Mathewson, Margie A; Ward, Samuel R; Chambers, Henry G et al. (2015) High resolution muscle measurements provide insights into equinus contractures in patients with cerebral palsy. J Orthop Res 33:33-9
Dayanidhi, Sudarshan; Dykstra, Peter B; Lyubasyuk, Vera et al. (2015) Reduced satellite cell number in situ in muscular contractures from children with cerebral palsy. J Orthop Res 33:1039-45
Mathewson, Margie A; Chambers, Henry G; Girard, Paul J et al. (2014) Stiff muscle fibers in calf muscles of patients with cerebral palsy lead to high passive muscle stiffness. J Orthop Res 32:1667-74
Smith, Lucas R; Chambers, Henry G; Lieber, Richard L (2013) Reduced satellite cell population may lead to contractures in children with cerebral palsy. Dev Med Child Neurol 55:264-70
Smith, Lucas R; Meyer, Gretchen; Lieber, Richard L (2013) Systems analysis of biological networks in skeletal muscle function. Wiley Interdiscip Rev Syst Biol Med 5:55-71
Tuttle, Lori J; Ward, Samuel R; Lieber, Richard L (2012) Sample size considerations in human muscle architecture studies. Muscle Nerve 45:742-5
Smith, Lucas R; Chambers, Henry G; Subramaniam, Shankar et al. (2012) Transcriptional abnormalities of hamstring muscle contractures in children with cerebral palsy. PLoS One 7:e40686
Gillies, Allison R; Smith, Lucas R; Lieber, Richard L et al. (2011) Method for decellularizing skeletal muscle without detergents or proteolytic enzymes. Tissue Eng Part C Methods 17:383-9
Smith, Lucas R; Lee, Ki S; Ward, Samuel R et al. (2011) Hamstring contractures in children with spastic cerebral palsy result from a stiffer extracellular matrix and increased in vivo sarcomere length. J Physiol 589:2625-39

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