Biomarkers of Tissue Tolerance and Behavior in a Rat Model

点击翻译按钮获取中文摘要

Abstract Repetitive overuse induced musculoskeletal injuries (MSKIs) are the leading cause of pain and physical disability worldwide. Treatment has proved difficult. We believe that 4 issues underlie this problem – (1) the frequent, yet incorrect, assumption that occupational physical activity is as equally beneficial as voluntary exercise; (2) a failure to consider how pathological processes vary and interact over time; (3) under- investigation of sex-linked differences and consequences of aging (“inflammaging” and reduced repair); and (4) overlooking what we hypothesize are key factors involved in the transition to chronicity, e.g., poor sleep and fibrotic/degenerative processes. It is time to take a fresh approach to reduce the enormous burden of MSKIs. One promising, non-pharmacological alternative is improved sleep, since poor sleep generates a systemic inflammatory response and lowers one's tolerance and threshold to painful stimuli. Another efficacious non- pharmacological intervention for MSKI pain is whole body aerobic exercise. Although the pain-relieving mechanisms of whole body general exercise remain unclear, evidence points to its capacity to lower systemic inflammation. Additionally, since idiopathic tendinopathies and compressive mononeuropathies are associated with increased pain and weakness, we hypothesize that tissue fibrosis is a key factor in the dysfunction with chronic overuse MSKIs. Although recovery from tissue fibrosis is typically thought to be slow or irreversible, we found that early treatment with novel anti-fibrotic agents, including anti-CTGF/CCN2 (anti-connective tissue growth factor/cell communication network factor 2, called FG-3019), reduced developing nerve and musculotendinous fibrosis, and remarkably reversed established widespread fibrosis and restored tissue structure and function in our rat model of overuse injuries. Aim 1, we will determine in young adult rats (3 mo of age at onset), using our operant model of overuse injuries: (a) causal pathways in overuse MSKIs, focusing on roles of poor sleep, tissue inflammation and fibrosis; (b) whether sleep has a role in moderating pain intensity/persistence; and (c) whether undisturbed sleep or whole body exercise, and reduced fibrosis using FG-3019, or a combination, effectively improves function and reduces pain. Aim 2, will be similar, except we will use very mature rats (15 mo of age). We hypothesize that poor sleep, low physical activity, psychological factors, and specific systemic inflammatory and fibrotic profiles, will increase the risk of pain and be predictive of poor recovery. We further hypothesize that in combination, improved sleep and general whole body exercise could have a cumulative anti-inflammation effect, and by impacting numerous bodily systems. Furthermore, if tissue fibrosis is also reduced, we hypothesize an acceleration of recovery and restoration of neuro- musculoskeletal function. Results are expected to provide new insight into causal pathways of chronic overuse MSKIs; how disruption of normal sleep adversely affects outcomes from injury, and pathways through which exercise positively impacts pain; and how aging influences these responses.