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Increased serum and musculotendinous fibrogenic proteins following persistent low-grade inflammation in a rat model of long-term upper extremity overuse.

Gao HG, Fisher PW, Lambi AG, Wade CK, Barr-Gillespie AE, Popoff SN, Barbe MF - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.

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.

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Pro- and anti-inflammatory cytokines in serum.Groups are as defined in figure legend 2. Data is shown for (A) TNF-alpha, (B) IL-6, (C) IL-10, (D), IL-1alpha, (E) IL-12 (only TR24 and 18 wk HRLF rat serum were tested for IL-12), and (F) MIP2. Symbols: *:p<0.05, **:p<0.01, compared to age-matched control rats. a: p<0.05, compared to age-matched trained rats that rested for 24 weeks after the initial training period.
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pone-0071875-g004: Pro- and anti-inflammatory cytokines in serum.Groups are as defined in figure legend 2. Data is shown for (A) TNF-alpha, (B) IL-6, (C) IL-10, (D), IL-1alpha, (E) IL-12 (only TR24 and 18 wk HRLF rat serum were tested for IL-12), and (F) MIP2. Symbols: *:p<0.05, **:p<0.01, compared to age-matched control rats. a: p<0.05, compared to age-matched trained rats that rested for 24 weeks after the initial training period.

Mentions: We next examined serum for these same and related cytokines to determine if there were concomitant increases in serum as in tissues. TNF-α and IL-6 were increased in serum of 24-week HRLF rats, compared to C rats (ANOVA results were p = 0.02 and 0.001, respectively; Fig. 4A,B). IL-6 was also higher in 24-week HRLF rats, compared to TR24 rats (Fig. 4B). IL-10, IL-1α and IL-12 were increased in serum of 18-week HRLF rats, compared to C rats (ANOVA results were p = 0.03, 0.03 and 0.02, respectively; Fig. 4C–E). Serum MIP2 levels trended higher in 18-week HRLF compared to C rats, but did not reach significance (ANOVA: p = 0.07; Fig. 4F). No serum increases were seen for IL-1β, IL-2, IL-4 or MIP3 (data not shown). There were also increases of TNF-α, IL-10, and IL-1α in the serum of TR0 rats, although there was high variability (and thus no significant increase).


Increased serum and musculotendinous fibrogenic proteins following persistent low-grade inflammation in a rat model of long-term upper extremity overuse.

Gao HG, Fisher PW, Lambi AG, Wade CK, Barr-Gillespie AE, Popoff SN, Barbe MF - PLoS ONE (2013)

Pro- and anti-inflammatory cytokines in serum.Groups are as defined in figure legend 2. Data is shown for (A) TNF-alpha, (B) IL-6, (C) IL-10, (D), IL-1alpha, (E) IL-12 (only TR24 and 18 wk HRLF rat serum were tested for IL-12), and (F) MIP2. Symbols: *:p<0.05, **:p<0.01, compared to age-matched control rats. a: p<0.05, compared to age-matched trained rats that rested for 24 weeks after the initial training period.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756034&req=5

pone-0071875-g004: Pro- and anti-inflammatory cytokines in serum.Groups are as defined in figure legend 2. Data is shown for (A) TNF-alpha, (B) IL-6, (C) IL-10, (D), IL-1alpha, (E) IL-12 (only TR24 and 18 wk HRLF rat serum were tested for IL-12), and (F) MIP2. Symbols: *:p<0.05, **:p<0.01, compared to age-matched control rats. a: p<0.05, compared to age-matched trained rats that rested for 24 weeks after the initial training period.
Mentions: We next examined serum for these same and related cytokines to determine if there were concomitant increases in serum as in tissues. TNF-α and IL-6 were increased in serum of 24-week HRLF rats, compared to C rats (ANOVA results were p = 0.02 and 0.001, respectively; Fig. 4A,B). IL-6 was also higher in 24-week HRLF rats, compared to TR24 rats (Fig. 4B). IL-10, IL-1α and IL-12 were increased in serum of 18-week HRLF rats, compared to C rats (ANOVA results were p = 0.03, 0.03 and 0.02, respectively; Fig. 4C–E). Serum MIP2 levels trended higher in 18-week HRLF compared to C rats, but did not reach significance (ANOVA: p = 0.07; Fig. 4F). No serum increases were seen for IL-1β, IL-2, IL-4 or MIP3 (data not shown). There were also increases of TNF-α, IL-10, and IL-1α in the serum of TR0 rats, although there was high variability (and thus no significant increase).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.

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.

Show MeSH
Related in: MedlinePlus