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

Abstract

Key clinical features of cumulative trauma disorders include pain, muscle weakness, and tissue fibrosis, although the etiology is still under investigation. Here, we characterized the temporal pattern of altered sensorimotor behaviors and inflammatory and fibrogenic processes occurring in forearm muscles and serum of young adult, female rats performing an operant, high repetition high force (HRHF) reaching and grasping task for 6, 12, or 18 weeks. Palmar mechanical sensitivity, cold temperature avoidance and spontaneous behavioral changes increased, while grip strength declined, in 18-week HRHF rats, compared to controls. Flexor digitorum muscles had increased MCP-1 levels after training and increased TNFalpha in 6-week HRHF rats. Serum had increased IL-1beta, IL-10 and IP-10 after training. Yet both muscle and serum inflammation resolved by week 18. In contrast, IFNγ increased at week 18 in both muscle and serum. Given the anti-fibrotic role of IFNγ, and to identify a mechanism for the continued grip strength losses and behavioral sensitivities, we evaluated the fibrogenic proteins CCN2, collagen type I and TGFB1, as well as the nociceptive/ fibrogenic peptide substance P. Each increased in and around flexor digitorum muscles and extracellular matrix in the midforearm, and in nerves of the forepaw at 18 weeks. CCN2 was also increased in serum at week 18. At a time when inflammation had subsided, increases in fibrogenic proteins correlated with sensorimotor declines. Thus, muscle and nerve fibrosis may be critical components of chronic work-related musculoskeletal disorders. CCN2 and substance P may serve as potential targets for therapeutic intervention, and CCN2 as a serum biomarker of fibrosis progression.

Manual therapy as an effective treatment for fibrosis in a rat model of upper extremity overuse injury

“…A power analysis was performed using Statview using prior tissue TGF-β1 and grip strength data (Abdelmagid, Barr et al 2012, Fisher, Zhao et al 2015). We chose the most conservative sample size needed to detect differences with an alpha level of 0.05 and 80% power.…”

“…We observed exposure-dependent declines in sensorimotor function after short-term performance of these tasks (≤3 months), with a high repetition high force (HRHF) task inducing the greatest dysfunction (Fedorczyk, Barr et al 2010, Barbe, Gallagher et al 2013, Fisher, Zhao et al 2015). We have shown that ibuprofen administered in weeks 5–6 of a 6-week HRHF task, or in weeks 5–12 of a 12-week HRHF task, attenuated inflammatory responses that drove tissue fibrosis (Abdelmagid, Barr et al 2012, Jain, Barr-Gillespie et al 2014).…”

“…We have developed a unique rodent model of operant repetitive reaching and grasping in which the performance of a reaching and handle-pulling task causes injury and inflammation, followed by nerve, muscle and connective tissue fibrosis, and then compressive nerve pathology with reduced nerve conduction velocity (Clark, Barr et al 2003, Clark, Al Shatti et al 2004, Elliott, Barr et al 2009, Elliott, Barr et al 2009, Elliott, Barr et al 2010, Fedorczyk, Barr et al 2010, Abdelmagid, Barr et al 2012, Gao, Fisher et al 2013, Jain, Barr-Gillespie et al 2014, Fisher, Zhao et al 2015). We observed exposure-dependent declines in sensorimotor function after short-term performance of these tasks (≤3 months), with a high repetition high force (HRHF) task inducing the greatest dysfunction (Fedorczyk, Barr et al 2010, Barbe, Gallagher et al 2013, Fisher, Zhao et al 2015).…”

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]).…”