We examined the relationship between grip strength declines and muscle-tendon responses induced by long-term overall performance of a high-repetition low-force (HRLF) reaching task in rats. Comparable 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 muscle tissue tendons and serum and TNF-α in muscle tissue and serum. Four fibrogenic proteins TGFB1 CTGF PDGFab Rabbit Polyclonal to GUF1. and PDGFbb and hydroxyproline a marker of collagen synthesis increased in serum in HRLF weeks 18 Torcetrapib or 24 concomitant with epitendon thickening increased muscle mass and tendon TGFB1 and CTGF. A collagenolytic gelatinase MMP2 increased by week 18 in Torcetrapib serum tendons and muscle tissue of HRLF rats. Grip strength correlated inversely with TGFB1 in muscle tissue tendons and serum; with CTGF-immunoreactive fibroblasts in tendons; and Torcetrapib with MMP2 in tendons and serum. Thus motor declines correlated with low-grade systemic and musculotendinous inflammation throughout task overall performance and increased fibrogenic and degradative proteins with prolonged task overall 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. Introduction According to the Bureau of Labor Statistics report entitled Nonfatal Occupational Injuries and Illnesses Requiring Days Away from Work 2011 musculoskeletal disorders accounted for 33 percent of all lost work time workplace injuries and illnesses in the U.S. and required a median of 11 days away from work . Studies in humans with upper extremity work-related musculoskeletal disorders find evidence of inflammation fibrosis and degeneration in serum and musculotendinous tissues changes thought to induce concurrent motor dysfunction -. However the pathophysiological responses are still under investigation particularly responses associated with chronic myopathies and tendinopathies as are serum biomarkers that might aid in pinpointing the stage of these disorders. An inflammatory response in musculoskeletal tissues has been considered an important element in the pathogenesis of upper extremity soft tissue disorders -. A small number of studies have searched for and detected serum biomarkers of inflammation in patients with upper extremity musculoskeletal disorders of short duration (<3 months) including C-reactive protein interleukin- 6 (IL-6) tumor necrosis factor-alpha (TNF-α) and users of the IL-1 family   . The results of these studies suggest a role for inflammatory cytokines early in the course of upper extremity MSDs. However tissues collected from patients with upper extremity MSDs at the time of surgical intervention show increased IL-1β immunoreactive fibroblasts and IL-6 (which can be pro- or anti-inflammatory depending on accompanying cytokines) - but few acute inflammatory responses  . Interestingly IL-6 IL-1β and TNF-α have also been deemed as pro-fibrotic cytokines due to their mitogenic and chemotactic effects Torcetrapib on fibroblasts and induction of fibrogenic proteins -. A few studies examining serum of workers have also detected increased serum biomarkers of collagen turnover in response to prolonged exposure to heavy physical loads. Increased serum markers of collagen type I synthesis (PINP; N-terminal propeptide type I procollagen) and degradation (CTX1; C-telopeptide of type I collagen) were identified in workers employed in heavy manual lifting jobs - although the overall ratio of these synthesis to degradation markers remained the same in male construction workers as in workers with sedentary jobs. These results indicate that stressed tissues can adapt to the requires of a particular job increasing collagen synthesis to match that of collagen degradation. However studies examining tendosynovial tissues collected from patients with upper extremity musculoskeletal disorders during surgical intervention show increased tissue fibrogenic and degradative proteins (e.g. transforming growth factor beta 1 and matrix metalloproteases) and fibrotic histopathology     . These latter findings are indicative of deranged extracellular matrix production and degeneration in tissues by the time of surgical intervention rather than tissue adaptation. Transforming growth factor beta 1 (TGFB1) and connective tissue growth factor (CTGF/CCN2) are important mediators of fibrosis. TGFB1 has been implicated as a sensitive serum biomarker of fibrogenic tissues changes . Levels of CTGF/CCN2 in patients with scleroderma or other fibrotic disorders.