Increased Serum and Musculotendinous Fibrogenic Proteins following Persistent Low-Grade Inflammation in a Rat Model of Long-Term Upper Extremity Overuse

Abstract

We examined the relationship between grip strength declines and muscle-tendon responses induced by long-term performance of a high-repetition, low-force (HRLF) reaching task in rats. We hypothesized that grip strength declines would correlate with inflammation, fibrosis and degradation in flexor digitorum muscles and tendons. Grip strength declined after training, and further in weeks 18 and 24, in reach limbs of HRLF rats. Flexor digitorum tissues of reach limbs showed low-grade increases in inflammatory cytokines: IL-1β after training and in week 18, IL-1α in week 18, TNF-α and IL-6 after training and in week 24, and IL-10 in week 24, with greater increases in tendons than muscles. Similar cytokine increases were detected in serum with HRLF: IL-1α and IL-10 in week 18, and TNF-α and IL-6 in week 24. Grip strength correlated inversely with IL-6 in muscles, tendons and serum, and TNF-α in muscles and serum. Four fibrogenic proteins, TGFB1, CTGF, PDGFab and PDGFbb, and hydroxyproline, a marker of collagen synthesis, increased in serum in HRLF weeks 18 or 24, concomitant with epitendon thickening, increased muscle and tendon TGFB1 and CTGF. A collagenolytic gelatinase, MMP2, increased by week 18 in serum, tendons and muscles of HRLF rats. Grip strength correlated inversely with TGFB1 in muscles, tendons and serum; with CTGF-immunoreactive fibroblasts in tendons; and with MMP2 in tendons and serum. Thus, motor declines correlated with low-grade systemic and musculotendinous inflammation throughout task performance, and increased fibrogenic and degradative proteins with prolonged task performance. Serum TNF-α, IL-6, TGFB1, CTGF and MMP2 may serve as serum biomarkers of work-related musculoskeletal disorders, although further studies in humans are needed.

Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury

“…Adjacent sections of the NC, FRC and 18-week HRHF rat muscles were stained with hematoxylin and eosin (H&E), and with CD11b (a macrophage marker), using previously described methods (Fedorczyk et al 2010;Gao et al 2013). These sections were examined for the presence of neutrophils, lymphocytes or macrophages.…”

Ibuprofen as a Treatment for Work-Related Musculoskeletal Disorders: Effectiveness versus Caveats

“…Evidence of tissue injury was paralleled by inlammatory responses, such as increased pro-inlammatory cytokines in lexor digitorum muscles and tendons [30][31][32]39], and increased macrophages in the median nerve at the level of the wrist (Figure 3A, B). Elevated levels of key pro-inlammatory cytokines, IL-1beta, and TNF-alpha were also observed in serum of rats that had performed a HRHF task for 12 weeks (12-week HRHF rats) ( Figure 3D, E).…”

“…Those suggested maximum limits are indicated in Table 1. 4. An operant rat model of WMSD Several animal models have been developed to study WMSDs and have shown that repetitive hand activities induce sensorimotor dysfunction [27][28][29][30][31][32][33]. A model developed in our laboratory is a unique operant rat model of voluntary reaching and grasping (Figure 1; [7,34]).…”

“…Using this rat model, we have observed early exposure-dependent changes (duration and task level) in inlammatory responses in the form of increased macrophages and inlammatory cytokines in soft tissues involved in performing the repetitive task [7,30,32,35,36]. The greatest responses were observed in rats performing a high-repetition high-force (HRHF) task for 6-12 weeks, compared to lower demand tasks.…”

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).…”