Voluntary running attenuates behavioural signs of low back pain: dimorphic regulation of intervertebral disc inflammation in male and female SPARC-null mice.

OBJECTIVE: To examine the effect of running exercise on behavioral measures of pain and intervertebral disc (IVD) inflammation in the SPARC-null mouse model. METHODS: Male and female 8-month old SPARC-null and age-matched control mice received a home cage running wheel or a control, fixed wheel for 6 months. Behavioral assays were performed to assess axial discomfort (grip test) and radiating leg pain (von Frey, acetone tests) and voluntary running was confirmed. Expression of inflammatory mediators (TNF-α, IL-1ß, IL-2, IL-10, CCL5, CXCL1, CXCL5, RANKL, M-CSF, and VEGF) in IVDs was determined. Additional inflammatory (IL-1ß, IL-1Ra, CXCR1, CXCR2) and macrophage phenotypic markers (ITGAM, CD80, CD86, CD206, Arg1) in IVDs were investigated by qPCR. RESULTS: Voluntary running attenuated behavioral measures of pain in male and female SPARC-null mice. Increases in mediators including IL-1ß, CXCL1 and CXCL5 were observed in SPARC-null compared to control IVDs. After 6 months of running, increases in M-CSF and VEGF were observed in male SPARC-null IVDs. In females, pro-inflammatory mediators, including CXCL1 and CXCL5 were downregulated by running in SPARC-null mice. qPCR analysis further confirmed the anti-inflammatory effect of running in female IVDs with increased IL-1Ra mRNA. Running induced upregulation of the macrophage marker ITGAM mRNA in males. CONCLUSIONS: Voluntary running reversed behavioral signs of pain in male and female mice and reduced inflammatory mediators in females, but not males. Thus, the therapeutic mechanism of action may be sex-specific.

ISSLS Prize in Basic science 2019: Physical activity attenuates fibrotic alterations to the multifidus muscle associated with intervertebral disc degeneration.

PURPOSE: Chronic low back pain causes structural remodelling and inflammation in the multifidus muscle. Collagen expression is increased in the multifidus of humans with lumbar disc degeneration. However, the extent and mechanisms underlying the increased fibrotic activity in the multifidus are unknown. Physical activity reduces local inflammation that precedes multifidus fibrosis during intervertebral disc degeneration (IDD), but its effect on amelioration of fibrosis is unknown. This study aimed to assess the development of fibrosis and its underlying genetic network during IDD and the impact of physical activity. METHODS: Wild-type and SPARC-null mice were either sedentary or housed with a running wheel, to allow voluntary physical activity. At 12 months of age, IDD was assessed with MRI, and multifidus muscle samples were harvested from L2 to L6. In SPARC-null mice, the L1/2 and L3/4 discs had low and high levels of IDD, respectively. Thus, multifidus samples from L2 and L4 were allocated to low- and high-IDD groups compared to assess the effects of IDD and physical activity on connective tissue and fibrotic genes. RESULTS: High IDD was associated with greater connective tissue thickness and dysregulation of collagen-III, fibronectin, CTGF, substance P, TIMP1 and TIMP2 in the multifidus muscle. Physical activity attenuated the IDD-dependent increased connective tissue thickness and reduced the expression of collagen-I, fibronectin, CTGF, substance P, MMP2 and TIMP2 in SPARC-null animals and wild-type mice. Collagen-III and TIMP1 were only reduced in wild-type animals. CONCLUSIONS: These data reveal the fibrotic networks that promote fibrosis in the multifidus muscle during chronic IDD. Furthermore, physical activity is shown to reduce fibrosis and regulate the fibrotic gene network. These slides can be retrieved under Electronic Supplementary Material.

Short-chain fatty acid enemas fail to decrease colonic hypersensitivity and inflammation in TNBS-induced colonic inflammation in rats.

BACKGROUND AND AIMS: Short-chain fatty acid (SCFA) (especially butyrate) enemas are widely used to reduce symptoms associated with human inflammatory bowel disease. The purpose of this study was to evaluate their real effect on colonic sensitivity in rats. METHODS: The effects of saline and SCFA enemas (acetate, propionate and particularly butyrate) were studied on visceral pain thresholds following colonic distension in control rats and in rats with colitis (instilled with trinitrobenzene sulfonic acid (TNBS)). RESULTS: Butyrate enemas (40 mM twice daily for 14 days) decreased colonic pain thresholds in control rats; they did not reduce the TNBS-induced hypersensitivity, but on the contrary increased its duration (without modifying the inflammation score). This pronociceptive effect was confirmed in control rats receiving twice daily enemas of 80 mM for 3 days and two enemas of 240 mM of a butyrate solution. The other SCFA enemas did not modify the hypersensitivity of rats with colitis and induced proinflammatory effects. CONCLUSIONS: The beneficial effect of SCFA (especially butyrate) enemas on hypersensitivity and inflammation in inflammatory bowel disease is questionable and needs to be thoroughly investigated in humans.