Aging Contributes to Inflammation in Upper Extremity Tendons and Declines in Forelimb Agility in a Rat Model of Upper Extremity Overuse

Abstract

We sought to determine if tendon inflammatory and histopathological responses increase in aged rats compared to young rats performing a voluntary upper extremity repetitive task, and if these changes are associated with motor declines. Ninety-six female Sprague-Dawley rats were used in the rat model of upper extremity overuse: 67 aged and 29 young adult rats. After a training period of 4 weeks, task rats performed a voluntary high repetition low force (HRLF) handle-pulling task for 2 hrs/day, 3 days/wk for up to 12 weeks. Upper extremity motor function was assessed, as were inflammatory and histomorphological changes in flexor digitorum and supraspinatus tendons. The percentage of successful reaches improved in young adult HRLF rats, but not in aged HRLF rats. Forelimb agility decreased transiently in young adult HRLF rats, but persistently in aged HRLF rats. HRLF task performance for 12 weeks lead to increased IL-1beta and IL-6 in flexor digitorum tendons of aged HRLF rats, compared to aged normal control (NC) as well as young adult HRLF rats. In contrast, TNF-alpha increased more in flexor digitorum tendons of young adult 12-week HRLF rats than in aged HRLF rats. Vascularity and collagen fibril organization were not affected by task performance in flexor digitorum tendons of either age group, although cellularity increased in both. By week 12 of HRLF task performance, vascularity and cellularity increased in the supraspinatus tendons of only aged rats. The increased cellularity was due to increased macrophages and connective tissue growth factor (CTGF)-immunoreactive fibroblasts in the peritendon. In conclusion, aged rat tendons were overall more affected by the HRLF task than young adult tendons, particularly supraspinatus tendons. Greater inflammatory changes in aged HRLF rat tendons were observed, increases associated temporally with decreased forelimb agility and lack of improvement in task success.

Prolonged performance of a high repetition low force task induces bone adaptation in young adult rats, but loss in mature rats

“…However, much greater increases in inflammatory cytokines were seen in forelimb bones of mature HRLF rats. This results are similar to our prior reports of increased inflammatory cytokine in tendons and serum of mature HRLF rats, compared to young adult HRLF rats [43, 49]. Increased inflammatory cytokine level variations in bones are known to affect both bone formation and resorption [32, 34, 35, 87, 90].…”

“…We next analyzed inflammatory cytokine levels in forelimb bones (radius and ulna), since we have reported increased pro-inflammatory cytokines in serum and tendons of mature HRLF rats, compared to young adult counterparts [49, 70], and since inflammatory cytokine levels are known to stimulate osteoclastogenesis [30–34]. Levels of each pro-inflammatory cytokine examined (IL-1beta, TNF-alpha and IL-6) were higher in mature HRLF rat bones (Fig.…”

“…This marginal increase was apparently not enough to trigger an osteogenic bone response and also failed to rescue maximum reflexive grip strength declines. Regarding the maximum reflexive grip strength declines, we have previously shown that increased inflammatory cytokines in serum, nerves and tendons of mature HRLF rats correlated with declines in maximum reflexive grip strength [49, 70, 94]. The decrease in maximum reflexive grip strength in the mature rats appears to be a myalgia-generated or even central sensitization pain response, as reported previously [54, 58, 94–96], that did not affect the mature HRLF rats’ abilities to perform this submaximal grasping task in which the HRLF rats had to reach at 15% of their maximum grip strength (see Table 1).…”

“…In contrast, performance of a high repetition high force (HRHF) task for 12 weeks by young adult rats leads to significant losses in trabecular bone volume and cortical thinning are in the radius, concomitant with higher and more sustained increases in inflammatory cytokines [46–48]. Although we have yet to examine the response of bones to prolonged performance of a repetitive tasks in mature rats (14–18 mo of age), similar aged rats have increased inflammatory cytokines in serum and tendons after a 12-week high repetition low force (HRLF) task, compared to young adult rats performing the same task [43, 49]. The inflammatory cytokines were the same that affect bone cell homeostasis and induce net bone loss (interleukin-1beta and tumor necrosis factor alpha) [32, 33, 50].…”

Systematic review of biochemical biomarkers for neck and upper-extremity musculoskeletal disorders

“…Comparatively fewer authors have researched MSD biomarkers in younger subjects with incipient disorders (40,41). Animal models would suggest that different biomarkers are present at different MSD stages and may differ by age (87)(88)(89). Various theories of MSD pathophysiology also suggest that differing biochemical biomarkers would occur at different MSD stages (21,82,90).…”