Work-related musculoskeletal disorders account for 30% of lost work time illnesses, yet, the pathophysiological mechanisms underlying their development and persistence over time is incompletely understood. The long term goal of this work is to use an innovative model of upper limb overuse injury in the rat to identify and characterize cellular mechanisms underlying tissue changes and behavioral sequelae associated with the performance of repetitive and/or forceful reaching.
The specific aims for this project are: 1) To determine the mechanisms whereby long-term exposure to two task regimens, medium repetition-low force (MRLF) and high repetition-high force (HRHF), leads to bone resorption and pathological changes, and articular cartilage damage, and if the mechanism underlying these changes is inflammatory, mechanical overuse, or both. 2) To determine the mechanisms whereby long-term exposure to two task regimens, MRLF and HRHF, leads to fibrosis and pathological degeneration in musculotendinous and neural tissues and if the mechanism underlying these changes is inflammatory, mechanical overuse, or both. 3) To determine if there is a relationship between biomarkers of tissue changes and sensorimotor function after exposure to two task regimens, MRLF and HRHF. Rats will be trained to perform a voluntary reaching and grasping task at MRLF (8 reaches per minute @ 5% maximum voluntary pulling force, MPF), or HRHF (12 reaches per minute at 60% MPF). Two experimental groups will receive either anti-tumor necrosis factor alpha or interleukin-1 receptor antagonist prophylactically in order to block inflammation. Musculoskeletal tissues, peripheral nerve and serum will be analyzed for cellular and biochemical markers of tissue inflammation and degeneration using a post-test control group design. Median nerve function will be tested and analyzed also using a post-test control group design. Behavioral variables indicative of reach performance and movement coordination will be analyzed for changes over time using a repeated measures design. To determine the association between serum and behavioral variables, a multiple regression analysis will be used. The 2 experimental groups will perform either the MRLF or HRHF task for 16 or 22 weeks. At each weekly endpoint, all animals will undergo sensorimotor performance testing and will then be split randomly into 3 subgroups for microscopic examination, protein analysis and median nerve conduction velocity testing (n=5-10 per group per analysis type at all weekly endpoints). Trained controls, matched by age, diet, and weight, will be sacrificed at matched time points for comparison to experimental animals. Forelimb tissues will be collected bilaterally and prepared for the various analyses These experiments will enhance our understanding of the effects of long-term exposure to combinations of risk factors (repetition and force) on tissue and function, as well as mechanisms (mechanical overload, or inflammation-induced catabolism/fibrosis) underlying those responses (degeneration, pain and loss of function).

Public Health Relevance

This rat model of WMSD is uniquely able to draw parallels between tissue pathophysiology and behavioral responses resulting from exposure to a range of tasks that are clinically meaningful, because they have been derived from the clinical and epidemiological literature concerning this important occupational health problem. The data generated by these studies in the rat will ultimately contribute to the development of new strategies for effective prevention and management of overuse injuries by providing insights into and a framework for future translational studies of clinical populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056019-05
Application #
8265329
Study Section
Musculoskeletal Rehabilitation Sciences Study Section (MRS)
Program Officer
Panagis, James S
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$325,374
Indirect Cost
$107,699
Name
Temple University
Department
Other Health Professions
Type
Schools of Allied Health Profes
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Jain, N X; Barr-Gillespie, A E; Clark, B D et al. (2014) Bone loss from high repetitive high force loading is prevented by ibuprofen treatment. J Musculoskelet Neuronal Interact 14:78-94
Gao, Helen G L; Fisher, Paul W; Lambi, Alex G et al. (2013) Increased serum and musculotendinous fibrogenic proteins following persistent low-grade inflammation in a rat model of long-term upper extremity overuse. PLoS One 8:e71875
Driban, Jeffrey B; Barr, Ann E; Amin, Mamta et al. (2011) Joint inflammation and early degeneration induced by high-force reaching are attenuated by ibuprofen in an animal model of work-related musculoskeletal disorder. J Biomed Biotechnol 2011:691412
Xin, Dong L; Harris, Michelle Y; Wade, Christine K et al. (2011) Aging enhances serum cytokine response but not task-induced grip strength declines in a rat model of work-related musculoskeletal disorders. BMC Musculoskelet Disord 12:63
Kietrys, David M; Barr, Ann E; Barbe, Mary F (2011) Exposure to repetitive tasks induces motor changes related to skill acquisition and inflammation in rats. J Mot Behav 43:465-76