Biomarkers of Tissue Tolerance and Behavior in a Rat Model

Repetitive overuse induced musculoskeletal injuries (MSKls) 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) underinvestigation
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 MSKls,
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 nonpharmacological
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 MSKls, 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 MSKls, 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 neuromusculoskeletal
function, Results are expected to provide new insight into causal pathways of chronic overuse
MSKls; how disruption of normal sleep adversely affects outcomes from injury, and pathways through which
exercise positively impacts pain; and how aging influences these responses,

Grant Number: 5R01AR056019-16
NIH Institute/Center: NIH
Principal Investigator: Mary Barbe