Biomarkers of Tissue Tolerance and Behavior in a Rat Model

摘要 重复过度使用引起的肌肉骨骼损伤（MSKI）是疼痛和身体损伤的主要原因。 全世界的残疾人。治疗已证明是困难的。我们认为，这一问题背后有四个问题：（1） 经常，但不正确的假设，职业体育活动是同样有益的自愿 （2）未能考虑病理过程如何随时间变化和相互作用;（3）在- 调查与性别相关的差异和衰老的后果（"炎症"和修复减少）;以及（4） 忽视了我们假设的慢性化的关键因素，例如，睡眠不足和 纤维化/退化过程。现在是时候采取新的方法来减轻MSKI的巨大负担了。 一种有希望的非药物替代方法是改善睡眠，因为睡眠不好会产生全身性的 炎症反应和降低一个人的耐受性和疼痛刺激的阈值。另一个有效的非- MSKI疼痛的药物干预是全身有氧运动。虽然止痛药 全身一般运动的机制尚不清楚，证据表明其降低系统性 炎症此外，由于特发性肌腱病和压迫性单神经病与 随着疼痛和虚弱的增加，我们假设组织纤维化是功能障碍的关键因素， 慢性过度使用MSKIs。虽然组织纤维化的恢复通常被认为是缓慢或不可逆的，但我们认为， 发现早期用新型抗纤维化药物治疗，包括抗CTGF/CCN 2（抗结缔组织增生）， 生长因子/细胞通讯网络因子2，称为FG-3019），减少了发育中的神经和 肌肉肌腱纤维化，并显着逆转建立广泛的纤维化和恢复组织 过度使用损伤大鼠模型的结构和功能。目的1，我们将确定在年轻的成年大鼠（3个月的 发病年龄），使用我们的过度使用损伤的操作模型：（a）过度使用MSKI的因果途径，重点是 睡眠不良、组织炎症和纤维化的作用;（B）睡眠是否在减轻疼痛中起作用 强度/持久性;以及（c）无论是不受干扰的睡眠还是全身锻炼， FG-3019或其组合可有效改善功能并减轻疼痛。目标2，将是类似的，除了我们 将使用非常成熟的大鼠（15月龄）。我们假设睡眠不好，身体活动少，心理 因素，以及特定的全身炎症和纤维化特征，将增加疼痛的风险， 恢复不佳。我们进一步假设，睡眠改善和全身锻炼相结合， 可能具有累积的抗炎作用，并通过影响许多身体系统。此夕h如果 组织纤维化也减少，我们假设加速恢复和恢复神经- 肌肉骨骼功能结果有望为慢性过度使用的因果途径提供新的见解 MSKI;正常睡眠的中断如何对损伤的结果产生不利影响，以及通过哪些途径 运动对疼痛有积极影响;以及衰老如何影响这些反应。

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.