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The Interaction of Force and Repetition on Musculoskeletal and Neural Tissue Responses and Sensorimotor Behavior in a Rat Model of Work-Related Musculoskeletal Disorders

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The Interaction of Force and Repetition on Musculoskeletal and Neural Tissue Responses and Sensorimotor Behavior in a Rat Model of Work-Related Musculoskeletal Disorders

Mary F Barbe et al. BMC Musculoskelet Disord.

Abstract

Background: We examined the relationship of musculoskeletal risk factors underlying force and repetition on tissue responses in an operant rat model of repetitive reaching and pulling, and if force x repetition interactions were present, indicative of a fatigue failure process. We examined exposure-dependent changes in biochemical, morphological and sensorimotor responses occurring with repeated performance of a handle-pulling task for 12 weeks at one of four repetition and force levels: 1) low repetition with low force, 2) high repetition with low force, 3) low repetition with high force, and 4) high repetition with high force (HRHF).

Methods: Rats underwent initial training for 4-6 weeks, and then performed one of the tasks for 12 weeks, 2 hours/day, 3 days/week. Reflexive grip strength and sensitivity to touch were assayed as functional outcomes. Flexor digitorum muscles and tendons, forelimb bones, and serum were assayed using ELISA for indicators of inflammation, tissue stress and repair, and bone turnover. Histomorphometry was used to assay macrophage infiltration of tissues, spinal cord substance P changes, and tissue adaptative or degradative changes. MicroCT was used to assay bones for changes in bone quality.

Results: Several force x repetition interactions were observed for: muscle IL-1alpha and bone IL-1beta; serum TNFalpha, IL-1alpha, and IL-1beta; muscle HSP72, a tissue stress and repair protein; histomorphological evidence of tendon and cartilage degradation; serum biomarkers of bone degradation (CTXI) and bone formation (osteocalcin); and morphological evidence of bone adaptation versus resorption. In most cases, performance of the HRHF task induced the greatest tissue degenerative changes, while performance of moderate level tasks induced bone adaptation and a suggestion of muscle adaptation. Both high force tasks induced median nerve macrophage infiltration, spinal cord sensitization (increased substance P), grip strength declines and forepaw mechanical allodynia by task week 12.

Conclusions: Although not consistent in all tissues, we found several significant interactions between the critical musculoskeletal risk factors of force and repetition, consistent with a fatigue failure process in musculoskeletal tissues. Prolonged performance of HRHF tasks exhibited significantly increased risk for musculoskeletal disorders, while performance of moderate level tasks exhibited adaptation to task demands.

Figures

Figure 1
Figure 1
Inflammatory cytokines levels in flexor digitorum muscles tested using ELISA in week 0 (immediately following the training period) or after performing either a LRLF, HRLF, LRHF and HRHF task for 12 weeks. (A & D) Muscle TNFalpha in week 0 and 12. (B & E) Muscle IL-1beta in week 0 and 12. (C & F) Muscle IL-1alpha in week 0 and 12. Symbols: a and aa: p < 0.05 and p < 0.01, compared to LRLF rats; bb: p < 0.01, compared to HRLF rats; cc: p < 0.01, compared to LRHF rats; * and **: p < 0.05 and p < 0.01, compared to normal controls (NC) rats (indicated by dashed line). Mean and SEM are shown.
Figure 2
Figure 2
Inflammatory cytokines levels in flexor digitorum tendons tested using ELISA in week 0 (immediately following the training period) or after performing either a low repetition LRLF, HRLF, LRHF and HRHF task for 12 weeks. (A & D) Tendon TNFalpha in week 0 and 12. (B & E) Tendon IL-1beta in week 0 and 12. (C & F) Tendon IL-1alpha in week 0 and 12. Symbols: a and aa: p < 0.05 and p < 0.01, compared to LRLF rats; bb: p < 0.01, compared to HRLF rats; cc: p < 0.01, compared to LRHF rats; * and **: p < 0.05 and p < 0.01, compared to normal controls (NC) rats (indicated by dashed line). Mean and SEM are shown.
Figure 3
Figure 3
Inflammatory cytokines levels in radial and ulnar bones, and first row of carpal bones, tested using ELISA in week 0 (immediately following the training period) or after performing either a LRLF, HRLF, LRHF and HRHF task for 12 weeks. (A & D) Bone TNFalpha in week 0 and 12. (B & E) Bone IL-1beta in week 0 and 12. (C & F) Bone IL-1alpha in week 0 and 12. Symbols: a and aa: p < 0.05 and p < 0.01, compared to LRLF rats; b and bb: p < 0.05 and p < 0.01, compared to HRLF rats; * and **: p < 0.05 and p < 0.01, compared to food restricted controls (FRC) rats (indicated by dashed line). Mean and SEM are shown.
Figure 4
Figure 4
Serum inflammatory cytokine levels tested using ELISA in week 0 (immediately following the training period) or after performing either a low repetition low force (LRLF), high repetition low force (HRLF), low repetition high force (LRHF) and high repetition high force (HRHF) task for 12 weeks. (A & E) Tumor necrosis factor alpha (TNF-alpha) in weeks 0 and 12. (B & F) Interleukin 1-beta (IL-1beta) in weeks 0 and 12. (C & D) IL-1alpha in weeks 0 and 12. Symbols: aa: p < 0.01, compared to LRLF rats; bb: p < 0.01, compared to HRLF rats; cc: p < 0.01, compared to LRHF rats; **: p < 0.01, compared to normal controls (NC) rats (mean values of NC rats are indicated by dashed line). Mean and SEM are shown.
Figure 5
Figure 5
Peripheral and central neural responses examined using quantitative immunohistochemical methods in week 0 (immediately following the training period) or after performing either a LRLF, HRLF, LRHF and HRHF task for 12 weeks. (A & B) Mean number of ED1-immunoreactive (ED1-IH) macrophages in the median nerve at the level of the wrist, in week 0 and 12. (C & D) Representative photos of the median nerve at the level of the wrist, showing an absence of ED1-IH macrophages in a NC rat, but increased macrophages (stained black; arrows indicate a few) in a 12-wk HRHF rat. (E & F) Percent area with substance P immunoreactivity in the dorsal horns of lower cervical spinal cord segments, in week 0 and 12. Data for upper lamina (I and II) of the dorsal horns are presented. (G & H) Representative photos of the dorsal horn of lower cervical spinal cord segments, showing only low grade increases of substance P (SubP) immunoreactivity in a NC rat, but increased SubP in the upper lamina (arrows) in a 12-wk HRHF rat. Symbols: aa: p < 0.01, compared to LRLF rats; bb: p < 0.01, compared to HRLF rats; **: p < 0.01, compared to normal controls (NC) rats (indicated by dashed line). Mean and SEM are shown. Scale bars are as indicated.
Figure 6
Figure 6
Histopathology and production of repair proteins in flexor digitorum tendons and muscles after performance of either a LRLF, HRLF, LRHF and HRHF task for 12 weeks. (A) Representative photos of ED1-immunoreactive (ED1-IH) macrophages in muscles (M) in a normal control rat and a 12-week HRHF rat. Arrows indicate ED1-IH macrophages; the arrow with the asterisk indicates a myofiber that is smaller than the others and that contains an ED1-IH cell within the myofiber, both indicative of a degenerating myofiber. Eosin counterstain (pink) shows increased collagen matrix between myofibers, indicative of fibrosis. (B) Inducible heat shock protein 72 (HSP72) in muscles. (C) Combined tendon pathology scores for cellularity, cell shape, and collagen organization (Bonar scoring system used in which 12 is the total score). (D) HSP72 in tendons. (E) Transforming growth factor beta 1 (TGFB1) in tendons. (F) Representative photos of H&E stained tendons showing elongated tenocytes and parallel collagen fibrils in a normal control endotendon, but rounded cells (tenocytes but also likely to include macrophages) and disrupted collagen fibrils in a 12-week HRHF endotendon. Symbols: aa: p < 0.01, compared to LRLF rats; bb: p < 0.01, compared to HRLF rats; **: p < 0.01, compared to normal controls (NC) rats (indicated by dashed line). Mean and SEM are shown. Scale bars = 50 micrometers.
Figure 7
Figure 7
Bone responses, assayed using histomorphometry, micro-computerized tomography and ELISA, after performance of either a LRLF, HRLF, LRHF and HRHF task for 12 weeks. (A-B) Number of osteoblast and osteoclasts, normalized by bone surface (N.Ob./BS and N.Oc/BS), assayed using histomorphometry. (C-D) Serum levels of CTX1 and osteocalcin, serum biomarkers of bone formation and bone resorption, respectively, assayed using ELISA. (D-H) Micro-computerized tomography (MicroCT) results for trabecular bone volume (BV/TV) of trabecular bone located in the distal radial metaphysis, as well as trabecular number (Tb.N), trabecular separation (Tb.Sp.) and trabecular thickness (Tb.Th). (I) Representative transaxial views of the trabecular region of the distal radial metaphysis, captured using microCT scanning and reconstruction and then 3-D rendering, showing a significant loss of trabeculae in this region in 12-week HRHF rats, but not in FRC or 12-week LRHF rats. This region shown was used to generate the BV/TV data shown in panel G. Symbols: aa: p < 0.01, compared to LRLF rats; bb: p < 0.01, compared to HRLF rats; dd: p < 0.01, compared to HRHF rats; **: p < 0.01, compared to food restricted control (FRC) rats (mean FRC values are indicated by dashed line). Mean and SEM are shown.
Figure 8
Figure 8
Cartilage responses, assayed using histomorphometry and ELISA, after performance of either a LRLF, HRLF, LRHF and HRHF task for 12 weeks. (A) Summated Mankin score results, a histopathological scoring system used to assay changes in the distal radial articular cartilage. (B) Representative photos of the distal radial articular cartilage showing a pathological loss of Safranin O (pink) staining, tidemark changes (arrows), and presence of a subchondral cyst (asterisk) in a 12-week HRHF rat; changes absent in a FRC rat (left part of panel). This region was used to generate the data shown in panel E. (C) Serum levels of C1,2C, assayed using ELISA. Symbols: aa: p < 0.01, compared to LRLF rats; bb: p < 0.01, compared to HRLF rats; dd: p < 0.01, compared to HRHF rats; **: p < 0.01, compared to food restricted control (FRC) rats (mean FRC values are indicated by dashed line). Mean and SEM are shown. Scale bar = 50 micrometer.
Figure 9
Figure 9
Maximum reflexive grip strength and palmar mechanical sensation in the preferred reach limb, examined after performing either a LRLF, HRLF, LRHF and HRHF task for 12 weeks. (A & B) Maximum reflexive grip strength in grams (g) in week 0 and week 12. (C & D) Palmar mechanical sensation, tested as withdrawal thresholds to mechanical stimulation with a series of von Frey hairs, in week 0 and week 12. Symbols: a and aa: p < 0.05 and p < 0.01, compared to LRLF rats; **: p < 0.01, compared to normal controls rat data combined with NC/naïve data (indicated by dashed line). Mean and SEM are shown.
Figure 10
Figure 10
Force x repetition quadrants superimposed on a fatigue failure curve. Exposure of materials (tissues) to high force may result in failure within a fairly limited number of repetitions. As force exposure is decreased, tissues would be able to withstand many more repetitions before failure. This figure illustrates why a force-repetition interaction would be expected if tissues become damaged as the result of a fatigue failure process.

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