Skip to main content
Download PDF

Correlation between inflammatory cytokine expression in paraspinal tissues and severity of disc degeneration in individuals with lumbar disc herniation

BMC Musculoskeletal Disorders volume 24, Article number: 193 (2023) Cite this article

Abstract

Purpose

Previous animal studies have discovered dysregulation of the local inflammatory state as a novel mechanism to explain structural changes in paraspinal muscles in association with disc degeneration. This study aimed to determine whether the expression of inflammatory genes in the multifidus muscle (MM) differs between individuals with disc degeneration and non-degeneration, which may cause changes in the cross-sectional area (CSA) of paraspinal muscles and clinical outcomes.

Methods

Muscles were procured from 60 individuals undergoing percutaneous endoscopic lumbar discectomy for lumbar disc herniation (LDH). Total and functional CSAs and fatty degeneration of paraspinal muscles on ipsilateral and unilateral sides were measured. Gene expression was quantified using qPCR assays. Paired t-test and Pearson’s correlation analysis were used to compare the mean difference and associations, respectively.

Results

There were significant differences in total CSAs of paraspinal muscles and functional CSA and fatty degeneration of MM between ipsilateral and unilateral sides. Participants in the disc degeneration group displayed higher fat infiltration in MM. The expression of TNF was moderately correlated with total CSAs of paraspinal muscles and functional CSA and fatty degeneration of MM. The expression of IL-1β was strongly correlated with the total and functional CSA of MM. The expression of TGF-β1 was moderately correlated with the functional CSA of MM. The expression of TNF, IL-1β, and TGF-β1 was moderate to strongly correlated with clinical outcomes.

Conclusion

The results show that there were differences in the characteristics of paraspinal muscles between the ipsilateral and unilateral sides, which were affected by disc degeneration and the degree of fat infiltration. High-fat filtration and reduction of CSA of MM are associated with inflammatory dysfunction. There was evidence of a dysregulated inflammatory profile in MM in individuals with poor clinical outcomes.

Peer Review reports

Introduction

Paraspinal muscles, as the action muscles of the back, are responsible for stabilizing and moving the lumbar vertebral column, which includes the iliopsoas, multifidus muscle (MM), quadratus lumborum, and erector spinae muscle. Several recent studies have investigated the qualitative (e.g., fatty infiltration [1]) and quantitative (e.g., fiber-type transformation [2] and cross-sectional area (CSA) [3]) changes in paraspinal muscles in association with the degeneration of intervertebral discs (IVDs) (e.g., lumbar disc herniation (LDH)). These structural changes in paraspinal muscles also play an important role in low back pain (LBP). Three main mechanisms have been revealed for causing the structural changes in paraspinal muscles, including muscle disuse atrophy, muscle denervation, and dysregulated inflammatory response. Animal studies have indicated that the dysregulation of local inflammatory activity is the main potential contributor to fat and connective tissue accumulation in paraspinal muscles in association with IVD lesions/injuries (e.g., spontaneous degeneration of IVD [4, 5] and experimental IVD injury [2]), which includes the inhibition of paraspinal muscle activation during the acute phase [6] and the loss of slow-twitch muscle fibres, connective tissue accumulation, and fatty infiltration during the subacute and chronic phases of paraspinal muscle atrophy. However, there is a lack of investigation of the relationship between different grades of IVD degeneration in Pfirrmann scores and the structural changes of paraspinal muscles (e.g., increased fatty infiltration and reduced CSA) [7]. Therefore, investigation of the relationship in patients with LDH is required.

Interestingly, an active process mediated by an inflammatory response has been revealed in different pathologies in paraspinal muscles. Animal models provide evidence for proinflammatory cytokine expression (e.g., tumor necrosis factor (TNF)) [8, 9] and localization and polarization of macrophages in MM adipose tissue that could not only drive the accumulation of fibrosis [10] but also associate muscle fiber changes [2, 11]. A recent human study revealed that a dysregulated inflammatory response is associated with increased fatty infiltration in MM in patients with LDH [12]. However, the association between the changes in the CSA of paraspinal muscles and inflammatory dysregulation remains unclear. It is interesting to wonder whether inflammatory dysregulation could affect the qualitative and quantitative changes in MM on the ipsilateral side (referred to as the side of disc herniation). This proposal requires examination.

The aims of this study were (1) to determine the difference in the CSA of paraspinal muscles on the ipsilateral side and the unilateral side; (2) to evaluate whether the CSA of paraspinal muscles differs between individuals with disc degeneration and no degeneration; (3) to investigate whether the expression of genes for inflammatory marker(s) in MM differed between individuals with low and high fatty infiltration and was associated with the change in CSA in MM; and (4) to determine the relationship between the change in CSA/expression of genes for inflammatory marker(s) and clinical outcomes.

Materials and methods

Study design

Participants with chronic LBP and sciatica undergoing percutaneous endoscopic lumbar discectomy (PELD) surgery for LDH were enrolled in this prospective cohort study, which was approved by the Medical Research Ethics Committee. All experiments were performed with the approval of Institutional Medical Research Ethics Committee where participants had consented for surgically discarded tissue to be used for research. All participants consented to the use of their demographic data, radiological data, clinical scores, and paraspinal tissues for research.

Participants

A total of 60 participants with LDH who underwent PELD surgery for sciatica with chronic LBP from January 2020 to January 2021 were included. All the participants completed at least twelve months of follow-up following PELD surgery.

The inclusion criteria were as follows: (1) aged ≥ 18 years old; (2) herniated disc in the lumbar spine region L4-L5 as confirmed by magnetic resonance imaging (MRI); (3) clinical history (e.g., sciatica with LBP) and physical examination (e.g., straight-leg-raising test) consistent with the findings on CT or MRI; and (4) nonresponsive to at least three months of nonsurgical treatment on the pain.

The exclusion criteria were as follows: (1) history of spinal deformity, tumor, infection, spondylolisthesis, and cauda equina syndrome; (2) history of lumbar spine surgery (fusion, laminectomy, or discectomy); (3) previous and current use of hormones; (4) severe organic disease, systemic metabolic bone disease, lipodystrophy, and neuromuscular syndromes; and (5) declined to participate in the project.

Demographic data

Demographic data of the patients’ age, sex, body mass index (BMI), and duration of symptoms were collected.

Clinical assessment

After obtaining written consent, the participants were asked to complete two questionnaires at the time of preoperative and last follow-up postoperative screening. The questionnaires are: (1) Visual Analogue Scale (VAS; 0 - no pain; 10 - worst pain imaginable) of back pain and leg pain, and (2) Oswestry disability index (ODI; a validated tool for assessing function and disability on 10 items, each item was manually rated with 5 points for six possible responses (the first statement is marked the section score = 0; the last statement is marked the section score = 5), giving a potential score between 0 and 100%.

MRI acquisition

All participants’ MR images were obtained with a 3.0 T Trio Tim scanner (Siemens, Erlangen, Germany), and participants were positioned supine in the MRI device. Sagittal T2-weighted fast spin-echo (FSE), sagittal T1-weighted FSE, and axial T2-weighted scans were performed. The field of view (FOV), repetition time (TR)/echo time (TE), matrix size, slice thickness, slice per slab, and number of excitations (NEX) were 310 * 310 mm, 550 ms/9.6 ms, 320 * 320, 4.0 mm, 11, and 2, respectively, during the sagittal T1-weighted scan. The FOV, TR/TE, matrix size, slice thickness, slice per slab, and NEX were 310 * 310 mm, 2700 ms/97 ms, 320 * 320, 4.0 mm, 11, and 2, respectively, during the sagittal T2-weighted scan. The FOV, TR/TE, matrix size, slice thickness, slice per slab, and NEX were 210 * 210 mm, 3400 ms/102 ms, 320 * 320, 4.0 mm, 15, and 2, respectively, during the axial T2-weighted scan.

Imaging assessment

The Pfirrmann score was used to evaluate IVD degeneration [7]. Pfirrmann grade ≥ 3 was defined as disc degeneration [13], which was used to allocate the participants into the IVD degeneration (+) and non-degeneration (-).

The Kjaer method on the MRI scans was used to evaluate fat infiltration in MM [1]. Scores were allocated as “normal/mild” for estimates of 0–10% fat and fibrous tissue within the muscle, “slight” for 10–50% fat, and “severe” for > 50% fat. All the participants were allocated into low (normal/mild + slight) and high (severe) fat infiltration groups.

ImageJ software (version 1.53, National Institutes of Health, Bethesda, MD) was used to measure the quantitative measurements of paraspinal muscles, including the total (referring to the total muscles and fat) CSAs, functional (referring to fat-free) CSAs, and fatty degeneration of paraspinal muscles on the ipsilateral side (referring to the side of leg pain due to the compression of the nerve root by the herniation disc) and unilateral side. The total CSAs of the psoas muscle, MM, and erector spinae muscle were drawn from the outline of the muscle fascial boundary using the region of interest (ROI) at the L4-5 IVD level with axial T2-weighted MRI (Fig. 1). Functional CSA was calculated within the total CSA according to the method described by Fortin and Jeon et al. [14]. The ratio of functional CSA to total CSA was used to evaluate the fatty degeneration of the paraspinal muscles.

Fig. 1
figure 1

A 48-year-old male with disc herniation at L4-L5 (red arrow) (a) The CSA of the paraspinal muscles was measured by drawing the outline of the muscle fascial boundary using the range of interest (ROI) at the L4-L5 intervertebral disc level on axial T2-weighted MRI. (i) ROI of multifidus muscle; (ii) ROI of erector spinae muscle; (iii) ROI of psoas. (b) Measurement of the fatty degeneration of the multifidus muscle was performed using a threshold method. The procedure of percutaneous endoscopic lumbar discectomy (PELD) for treating disc herniation at the left side of the L4-L5 intervertebral disc level on axial T2-weighted MRI (blue line)

Full size image

Sample collection

A standard surgical approach was used for PELD through an endoscope (SPINENDOS GmbH, Munich, Germany). After exposing the lumbodorsal fascia, the muscle samples were harvested from the transversospinal corner of the deep MM from the ipsilateral side at the lumbar spine level of L4-L5 or L5-S1 via the endoscope according to Fig. 1. The samples were washed three times with PBS and placed in RNA later for storage at -20 °C. Once completing the sample collection, the endoscope was inserted into the herniation disc through the foraminal at the L4-L5 or L5-S1 IVD level.

Quantitative polymerase chain reaction (qPCR) assay and inflammatory markers

RNA was extracted from muscle using RNeasy Lipid Tissue Mini Kit and RNeasy Fibrous Tissue Mini Kit (QIAGEN, Germany), and cDNA was synthesized and purified using QuantiTech Reverse transcription kit (QIAGEN, Germany). The expression of inflammatory markers in MM was examined by qPCR and normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) transcript, which includes TNF, interleukin-1 beta (IL-1β), IL-15, and transforming growth factor beta 1 (TGF-β1) [12, 15] (Table 1).

Table 1 Cytokines and molecules involved in muscle and primer sequences used for quantitative polymerase chain reaction (qPCR) analysis
Full size table

Statistical analysis

All data are presented as the mean ± standard deviation (SD). Independent t-tests were used to compare quantitative measurements of paraspinal muscles and the expression of genetic markers between the disc degeneration and non-degeneration groups and between the low- and high-fat infiltration groups. A paired t-test was used to compare the clinical outcomes of VAS LBP and leg pain and ODI between preoperative and 12 months post-operative follow-up and the CSAs of paraspinal muscles, functional CSA and fatty degeneration of MM between ipsilateral and unilateral sides.

The normality of variables was evaluated. Pearson’s correlation analysis was used to test the relationships between the demographic data (including age, BMI and duration of pain), preoperative clinical scores (VAS LBP, VAS leg pain, and ODI), and expression of inflammatory markers in MM at the time of PELD surgery and the quantitative measurement data (including the total CSAs of psoas muscle, MM, and erector spinae muscle, and functional CSA and fatty degeneration of MM) on the ipsilateral side. Correlations less than 0.3, between 0.3 and 0.5, between 0.5 and 0.7, and greater than 0.7 are indicative of weak, moderate, strong, and very strong.

Interrater reliability was evaluated with intraclass correlation coefficients (ICCs) and their 95% confidence intervals (95% CIs). Values of ICC less than 0.5, between 0.5 and 0.75, between 0.75 and 0.9, and greater than 0.90 are indicative of poor, moderate, good, and excellent reliability, respectively [16]. SPSS v24.0 (SPSS Inc., Chicago, IL., USA) was used for the statistical analysis. A P value less than 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 60 patients with LDH (37 males and 23 females; age of 43.05 ± 10.88 years, range from 20 to 65 years; BMI 27.67 ± 3.56 kg/m2) who underwent PELD surgery were enrolled. The mean duration of pain was 33.41 weeks (range from 70 to 14 weeks). All patients were diagnosed with single-level herniation at L4-L5. Disc degeneration and no degeneration were diagnosed in 36 and 24 patients, respectively, by using the Pfirrmann grade. Low fat infiltration was diagnosed in 29 patients. As shown in Table 2, leg pain on the right side was detected in 24 patients, and leg pain on the left side was explored in 36 patients. The mean VAS LBP, VAS leg pain, and ODI scores were 7.82 ± 1.81, 7.42 ± 1.89, and 26.64 ± 9.90 preoperatively, respectively. All the participants completed 12 months follow-up.

Table 2 Demographic data of included patients
Full size table

Quantitative assessment of paraspinal muscles

The total CSAs of the psoas muscle, MM, and erector spinae muscle and the functional CSA and fatty degeneration of MM on the ipsilateral side (versus unilateral side) were 1480.69 ± 316.02 mm2 (versus 1528.65 ± 323.66 mm2), 928.35 ± 183.75 mm2 (versus 976.15 ± 223.98 mm2), 1341.90 ± 327.31 mm2 (versus 1445.13 ± 323.75 mm2), 742.87 ± 166.01 mm2 (versus 800.29 ± 207.51 mm2), and 0.80 ± 0.08 (versus 0.82 ± 0.09), respectively. The statistically significant differences in the total CSAs of the psoas muscle (P = 0.000), MM (P = 0.003), and erector spinae muscle (P = 0.000) and functional CSA (P = 0.000) and fatty degeneration of MM (P = 0.001) between the ipsilateral side and unilateral side are indicated in Table 3.

Table 3 Quantitative measurements of paraspinal muscles
Full size table

Comparison of quantitative data of paraspinal muscles and clinical outcomes between different disc degeneration/fat infiltration groups

Compared with the no degeneration group, participants in the disc degeneration group displayed higher fat infiltration in MM (P = 0.005). Participants with higher preoperative levels of fat infiltration in the MM displayed worse LBP (P = 0.000) and leg pain (P = 0.000) measured with the VAS, function as measured by the ODI (P = 0.000), a higher reduction of CSA of MM (P = 0.006), functional CSA (P = 0.007) and fatty degeneration of MM (P = 0.001) in the high-fat infiltration group (Table 3).

Association between demographic data and quantitative data of paraspinal muscles

There was no correlation between demographic data (including age, BMI, and duration of pain) and quantitative data of paraspinal muscles (including the total CSAs of the psoas muscle, MM, and erector spinae muscle and functional CSA and fatty degeneration of MM) on the unilateral side.

Age showed a moderate association with fatty degeneration of MM on the ipsilateral side (r=-0.347, P = 0.007). The duration of pain had a moderate negative correlation with the CSA of MM (r=-0.368, P = 0.041) and the functional CAS of MM (r=-0.478, P = 0.022) (Table 4).

Table 4 Pearson’s correlation coefficient between continuous variables
Full size table

Association between quantitative data of paraspinal muscles and clinical outcomes

Quantitative measurement data of paraspinal muscles (including the total CSAs of the psoas muscle, MM, and erector spinae muscle, and functional CSA and fatty degeneration of MM) on the unilateral side were not related to preoperative clinical outcomes (including VAS LBP, VAS leg pain, and ODI).

There was a negative association between the CSAs of MM (r=-0.228, P = 0.021) and the erector spinae muscle (r=-0.260, P = 0.044) on the ipsilateral side and VAS leg pain. There was a statistically significant correlation between CSA of MM on the ipsilateral side and ODI (r=-0.244, P = 0.026) (Table 4).

Association between inflammatory markers and quantitative measurements of MM on the ipsilateral side

The expression of TNF in MM was moderately correlated with the total CSAs of the psoas muscle (r=-0.364, P = 0.011), MM (r=-0.509, P = 0.000), and erector spinae muscle (r=-0.403, P = 0.004), functional CSA (r=-0.437, P = 0.002) and fatty degeneration of MM (r=-0.488, P = 0.000). The expression of IL-1β in MM was strongly correlated with the CSA of MM (r=-0.674, P = 0.000) and the functional CSA of MM (r=-0.691, P = 0.000). The expression of TGF-β1 was moderately correlated with the functional CSA of MM (r=-0.313, P = 0.046) (Table 4).

Comparison of inflammatory markers in the MM between different Disc Degeneration/Fat infiltration groups

TNF expression was greater in participants with high-fat infiltration than in those with low-fat infiltration (Table 3). There were no differences in the expression of IL-1β, IL-15, and TGF-β1 between the disc degeneration and no degeneration groups or between the low- and high-fat infiltration groups.

Association between inflammatory markers and clinical outcomes

The expression of TNF, IL-1β, and TGF-β1 in MM was moderately to strongly correlated with the clinical outcomes (TNF with clinical outcome: VAS LBP (r = 0.410, P = 0.004), VAS leg pain (r = 0.286, P = 0.049), and ODI (r = 0.502, P = 0.000); IL-1β with clinical outcomes: VAS LBP (r = 0.522, P = 0.000), VAS leg pain (r = 0.462, P = 0.001), and ODI (r = 0.449, P = 0.001); TGF-β1 with clinical outcomes: VAS LBP (r = 0.682, P = 0.000), VAS leg pain (r = 0.387, P = 0.012), and ODI (r = 0.354, P = 0.023)). There was no significant correlation between the expression of IL-15 in MM and clinical outcomes (including VAS LBP, VAS leg pain, and ODI) (Table 4).

Interrater reliability

There was good to excellent agreement in terms of interrater reliability for the quantitative measurements on the ipsilateral side (including CSA of psoas: 0.087 (0.856, 0.902), CSA of MM: 0.854 (0.839, 0.887), CSA of erector spinae muscle: 0.855 (0.841, 0.889), functional CSA of MM: 0.788 (0.771, 0.825), and fatty degeneration of MM: 0.813 (0.807, 0.854)) and unilateral side (including CSA of psoas: 0.901 (0.889, 0.928), CSA of MM 0.894 (0.876, 0.923), CSA of erector spinae muscle: 0.894 (0.876, 0.915), functional CSA of MM: 0.832 (0.804, 0.867), and fatty degeneration of MM: 0.845 (0.823, 0.888)).

Discussion

The results of this study provide evidence of the quantitative changes in paraspinal muscles between the ipsilateral side and unilateral side and a relationship between the CSA of paraspinal muscles and CSA of lean muscle and fatty in MM and inflammatory dysregulation in the local environment in patients with LDH. Data show a significant reduction in the CSAs of the paraspinal muscles on the ipsilateral sciatica only. There is evidence for the relationships between MM dysfunction and poor functional outcome preoperatively and between fat accumulation in MM and disc degeneration/inflammatory dysregulation in the local environment. Data also show a greater proinflammatory response in MM in individuals with high-fat infiltration. TNF is moderately associated with the quantitative measurements (the total CSAs of the psoas muscle, MM, and erector spinae muscle, and functional CSA and fatty degeneration of MM) on the ipsilateral side. Upregulation of a greater proinflammatory response in the MM in individuals with low CSAs and high-fat infiltration. These findings have potential implications for understanding the mechanisms underlying the paraspinal muscle changes associated with disc herniation in humans relative to animal models.

Quantitative data of paraspinal muscles on the ipsilateral and unilateral sides

LDH is associated with paraspinal muscle morphological changes comprising the size, type, and distribution of fibers, especially changes in MM [17]. The medial branch of the dorsal ramus of the segmental nerve innervated the paraspinal muscle, which could lead to structural changes in paraspinal muscles due to denervation, disuse, or an inflammatory response [3, 11, 18,19,20]. The lesion of the compressive nerve root by the herniated disc led to muscle fiber denervation, which could cause quantitative changes in the paraspinal muscles. Additionally, the persistent compression of the nerve root contributes to fatty infiltration and atrophy of muscle fibers supplied by that nerve [17]. Furthermore, increased fatty infiltration of MM occurred with a consistent reduction in muscle CSA. Taken together, these cascade actions indicate that individuals with LDH might already undergo a structural change in the paraspinal muscles [18, 21]. Of note, there was a significant reduction in the CSAs of paraspinal muscles on the ipsilateral side compared to the unilateral side [21,22,23], which is consistent with our results. It is interesting to wonder what the main mechanism for causing the structural changes of paraspinal muscles is and whether these changes will affect the clinical outcomes.

Spontaneous IVD degeneration or IVD injury can cause inflammatory dysregulation in the local environment and mechanical changes in the lumbar spine, which is considered to be the leading cause of the structural changes in paraspinal muscles [2, 4,5,6, 11, 24]. Although the LBP rat model has provided evidence for the relationship between IVD degeneration and fat infiltration of paraspinal muscles [25], the direct causal relationship between IVD degeneration and paraspinal muscle fatty infiltration and quantitative measurements is unclear. Our study showed that there was no significant association between disc degeneration and quantitative measurements on paraspinal muscle. One of the main explanations is that most of the patients who underwent PELD surgery for LDH had disc degeneration (Pfirrmann grade ≥ 3), which potentially affected the results.

Association between the changes in paraspinal muscles and clinical outcomes

At present, multiple studies have reported an association between the morphological changes of paraspinal muscles and the presence of LBP and leg pain and functional limitation, which are influenced by the duration of pain [26,27,28,29,30]. However, due to a lack of measurement at a specific level and ipsilaterally to the pain source, the notion that MM morphological changes are not strong predictors of LBP or leg pain is also supported by some earlier studies, which failed to detect the associations between structural changes in paraspinal muscles and the presence of LBP or the duration of existing LBP symptoms [31, 32]. The results of the present study provide evidence for the relationship between paraspinal muscle dysfunction and poor clinical outcomes (e.g., LBP, leg pain, and disability).

Proinflammatory cytokine expression in MM

These data showed that the greater expression of the pro-inflammatory cytokine TNF was elevated in MM of LDH patients with a high fatty infiltration (a high fatty degeneration rate) and reduction in the CSA of muscles, which provided evidence for explaining the bidirectional relationship between fat and TNF. Hence, it was supported that adipose tissue is the main source or promoter of TNF expression, and as the driver of adipogenesis, TNF expression also accelerated fat accumulation. Animal models of disc degeneration/injury have identified that the increased proportion of proinflammatory M1 macrophages due to greater TNF expression is significantly associated with fat and connective tissue accumulation in MM [2, 33]. The absence of TNF in human MM underlies the increased fibrotic activity in MM during chronic LBP [12]. A previous human study provided evidence for greater TNF expression in MM of LDH patients with high fatty infiltration [12]. Taken together, TNF from alternate sources promotes fat infiltration in the human context, rather than the converse.

IL-1β is a potent proinflammatory cytokine critical to multiple pathologies in the paraspinal muscles. Greater expression of IL-1β promotes muscle differentiation and plays a role in the early phases of myogenesis and reduction of fibrosis, which could lead to the reduction of CSA of muscle [10]. An animal study on an IVD lesion model showed that blocking the expression of IL-1β by exercise could have diverse fibrosis/fatty infiltration, and reduced IL-1β in MM after mesenchymal stem cell treatment is associated with attenuated/delayed development of the components of structural remodelling present in MM [5]. TGF-β isoforms are cytokines involved in a variety of cellular processes, including myofiber repair and regulation of connective tissue formation. TGF-β plays an essential role in the development of tissue fibrosis and is a molecular marker in the study of muscle fibrosis, which has been reported in the MM of LDH patients [34]. Greater expression of TGF-β promotes atrophy/slow-to-fast transformation and induces differentiation of myocytes into myofibroblasts. IL-15 is a skeletal muscle-derived cytokine with favourable effects on muscle mass and body composition. As an anabolic factor in muscle growth, greater expression of IL-15 induces an accumulation of myosin heavy chain (MHC) protein in differentiated myotubes and plays a role in muscle–adipose tissue interactions [35]. The changes in cytokine expression in MM in our study supported the translation of the findings from animal models to humans.

Proinflammatory cytokine expression with clinical outcome

Systemically, the expression of proinflammatory cytokines is increasingly recognized in chronic pain conditions, such as the elevation of TNF and IL-1β in chronic LBP. Previous studies supported that proinflammatory cytokines (including TNF and IL-1β) from adipose tissue have been implicated in the association between obesity and osteoarthritis [36, 37]. In obesity, paraspinal adipose tissue is considered the source of systemic proinflammatory cytokines, which could drive the accumulation and/or polarization of adipose tissue macrophages to low-grade chronic inflammation. Our investigation of the inflammatory state of MM revealed that local TNF and IL-1β expression could help explain both chronic pians (LBP and radicular pain) and provide an alternative mechanism for the quantitative changes of muscles in some individuals. Similar to our study, a recent study showed that the elevation of TNF and IL-1β in paraspinal tissues (including muscles and fat) in LDH patients was associated with high-fat infiltration with poor postoperative outcome [12, 15]. Moreover, a study showed that the upgraded expression of TNF in serum was associated with poor recovery in patients with LBP plus sciatica or not [38]. A previous study provided evidence supporting IL-1β as a potent inflammatory cytokine involved in the mechanism of allodynia and possibly in the development of postoperative chronic pain [15], which is consistent with our results. TGF-β1 was also reported to be a cytokine that plays an essential role in the development of tissue fibrosis and is a molecular marker in the study of muscle fibrosis. A clinical study showed that nerve root compression by LDH leads to multifidus atrophy, fibrosis, and increased TGF-β1 expression, which promote MM fibrosis and are associated with changes in pain and disability scores [34]. Although our study provided evidence for the cascade actions of the reduction of CSA in paraspinal muscles in patients with LDH and the association of high expression of proinflammatory cytokines and the reduction of CSA of paraspinal muscles with poor clinical outcomes, the potential underlying mechanisms remain unclear and warrant further investigation.

Methodological issues

There are also some shortcomings identified in this study that require a brief discussion. First, healthy participants as a control group are missing. Second, potential bias during sample collection during PELD surgery exists. The tissue samples collected for this study were only harvested from the ipsilateral side during PELD surgery. Despite all care in selecting areas to collect samples from, there is a possibility of tissue sampling error due to the difference between ipsilateral and unilateral sides. Third, only one T2-axial image on the level of L4-L5 was used for measuring the CSA of paraspinal muscles. Finally, the expression of the proteins was not measured. Future prospective studies should investigate the expression of marker(s) in paraspinal muscles using a randomized controlled design with a larger sample size.

Conclusion

This study demonstrated that there were differences in the characteristics of paraspinal muscles between the ipsilateral and unilateral sides in patients with LDH, which was affected by disc degeneration and the degree of fat infiltration in MM. Furthermore, the novel results presented here support the hypothesis that the high-fat filtration and reduction of CSA of MM are associated with inflammatory dysfunction. Finally, there was evidence of a dysregulated inflammatory profile in MM in individuals with poor clinical outcomes.

Data Availability

The datasets used and/or analysed during the current study available from the corresponding author (Xiaolong Chen) on reasonable request.

References

  1. Kjaer P, Bendix T, Sorensen JS, Korsholm L, Leboeuf-Yde C. Are MRI-defined fat infiltrations in the multifidus muscles associated with low back pain? BMC Med. 2007;5:2.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hodges PW, James G, Blomster L, Hall L, Schmid A, Shu C, Little C, Melrose J. Multifidus muscle changes after back Injury are characterized by structural remodeling of muscle, adipose and connective tissue, but not muscle atrophy: Molecular and Morphological evidence. Spine (Phila Pa 1976). 2015;40(14):1057–71.

    Article  PubMed  Google Scholar 

  3. Ranger TA, Cicuttini FM, Jensen TS, Peiris WL, Hussain SM, Fairley J, Urquhart DM. Are the size and composition of the paraspinal muscles associated with low back pain? A systematic review. Spine J. 2017;17(11):1729–48.

    Article  PubMed  Google Scholar 

  4. James G, Klyne DM, Millecamps M, Stone LS, Hodges PW. ISSLS Prize in Basic science 2019: Physical activity attenuates fibrotic alterations to the multifidus muscle associated with intervertebral disc degeneration. European spine journal: official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2019.

  5. James G, Millecamps M, Stone LS, Hodges PW. Dysregulation of the Inflammatory Mediators in the Multifidus muscle after spontaneous intervertebral disc degeneration SPARC-null mice is ameliorated by physical activity. Spine (Phila Pa 1976). 2018;43(20):E1184–94.

    Article  PubMed  Google Scholar 

  6. Hodges P, Holm AK, Hansson T, Holm S. Rapid atrophy of the lumbar multifidus follows experimental disc or nerve root injury. Spine. 2006;31(25):2926–33.

    Article  PubMed  Google Scholar 

  7. Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976). 2001;26(17):1873–8.

    Article  CAS  PubMed  Google Scholar 

  8. Bost F, Caron L, Marchetti I, Dani C, Le Marchand-Brustel Y, Binetruy B. Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage. Biochem J. 2002;361(Pt 3):621–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xu H, Sethi JK, Hotamisligil GS. Transmembrane tumor necrosis factor (TNF)-alpha inhibits adipocyte differentiation by selectively activating TNF receptor 1. J Biol Chem. 1999;274(37):26287–95.

    Article  CAS  PubMed  Google Scholar 

  10. James G, Sluka KA, Blomster L, Hall L, Schmid AB, Shu CC, Little CB, Melrose J, Hodges PW. Macrophage polarization contributes to local inflammation and structural change in the multifidus muscle after intervertebral disc injury. Eur spine journal: official publication Eur Spine Soc Eur Spinal Deformity Soc Eur Sect Cerv Spine Res Soc. 2018;27(8):1744–56.

    Article  Google Scholar 

  11. Hodges PW, James G, Blomster L, Hall L, Schmid AB, Shu C, Little C, Melrose J. Can proinflammatory cytokine gene expression explain multifidus muscle fiber changes after an intervertebral disc lesion? Spine. 2014;39(13):1010–7.

    Article  PubMed  Google Scholar 

  12. James G, Chen X, Diwan A, Hodges PW. Fat infiltration in the multifidus muscle is related to inflammatory cytokine expression in the muscle and epidural adipose tissue in individuals undergoing surgery for intervertebral disc herniation. Eur Spine J. 2021;30(4):837–45.

    Article  PubMed  Google Scholar 

  13. Sharma A, Lancaster S, Bagade S, Hildebolt C. Early pattern of degenerative changes in individual components of intervertebral discs in stressed and nonstressed segments of lumbar spine: an in vivo magnetic resonance imaging study. Spine (Phila Pa 1976). 2014;39(13):1084–90.

    Article  PubMed  Google Scholar 

  14. Jeon I, Kim SW, Yu D. Paraspinal muscle fatty degeneration as a predictor of progressive vertebral collapse in osteoporotic vertebral compression fractures. Spine J. 2022;22(2):313–20.

    Article  PubMed  Google Scholar 

  15. Chen X, Hodges PW, James G, Diwan AD. Do markers of inflammation and/or muscle regeneration in lumbar Multifidus muscle and Fat Differ between individuals with good or poor outcome following microdiscectomy for lumbar disc herniation? Spine (Phila Pa 1976). 2021;46(10):678–86.

    Article  PubMed  Google Scholar 

  16. Koo TK, Li MY. A guideline of selecting and reporting intraclass correlation coefficients for reliability research. J Chiropr Med. 2016;15(2):155–63.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cooley JR, Walker BF, Kjaer EMA, Jensen P, Hebert TS. Relationships between paraspinal muscle morphology and neurocompressive conditions of the lumbar spine: a systematic review with meta-analysis. BMC Musculoskelet Disord. 2018;19(1):351.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Franke J, Hesse T, Tournier C, Schuberth W, Mawrin C, LeHuec JC, Grasshoff H. Morphological changes of the multifidus muscle in patients with symptomatic lumbar disc herniation. J Neurosurg Spine. 2009;11(6):710–4.

    Article  PubMed  Google Scholar 

  19. Stein TP, Wade CE. Metabolic consequences of muscle disuse atrophy. J Nutr. 2005;135(7):1824S–8.

    Article  CAS  PubMed  Google Scholar 

  20. Valdivieso P, Franchi MV, Gerber C, Fluck M. Does a better perfusion of deconditioned muscle tissue release chronic low back Pain? Front Med (Lausanne). 2018;5:77.

    Article  PubMed  Google Scholar 

  21. Kim WH, Lee SH, Lee DY. Changes in the cross-sectional area of multifidus and psoas in unilateral sciatica caused by lumbar disc herniation. J Korean Neurosurg Soc. 2011;50(3):201–4.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zhao WP, Kawaguchi Y, Matsui H, Kanamori M, Kimura T. Histochemistry and morphology of the multifidus muscle in lumbar disc herniation: comparative study between diseased and normal sides. Spine (Phila Pa 1976). 2000;25(17):2191–9.

    Article  CAS  PubMed  Google Scholar 

  23. Hyun JK, Lee JY, Lee SJ, Jeon JY. Asymmetric atrophy of multifidus muscle in patients with unilateral lumbosacral radiculopathy. Spine (Phila Pa 1976). 2007;32(21):E598–602.

    Article  PubMed  Google Scholar 

  24. Brown SH, Gregory DE, Carr JA, Ward SR, Masuda K, Lieber RL. ISSLS prize winner: adaptations to the multifidus muscle in response to experimentally induced intervertebral disc degeneration. Spine. 2011;36(21):1728–36.

    Article  PubMed  Google Scholar 

  25. Huang Y, Wang L, Luo B, Yang K, Zeng X, Chen J, Zhang Z, Li Y, Cheng X, He B. Associations of Lumber Disc Degeneration with paraspinal muscles myosteatosis in Discogenic Low Back Pain. Front Endocrinol (Lausanne). 2022;13:891088.

    Article  PubMed  Google Scholar 

  26. Sun D, Liu P, Cheng J, Ma Z, Liu J, Qin T. Correlation between intervertebral disc degeneration, paraspinal muscle atrophy, and lumbar facet joints degeneration in patients with lumbar disc herniation. BMC Musculoskelet Disord. 2017;18(1):167.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Faur C, Patrascu JM, Haragus H, Anglitoiu B. Correlation between multifidus fatty atrophy and lumbar disc degeneration in low back pain. BMC Musculoskelet Disord. 2019;20(1):414.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Suri P, Fry AL, Gellhorn AC. Do muscle characteristics on lumbar spine magnetic resonance imaging or computed Tomography Predict Future Low Back Pain, physical function, or performance? A systematic review. PM R. 2015;7(12):1269–81.

    Article  PubMed  Google Scholar 

  29. Barker KL, Shamley DR, Jackson D. Changes in the cross-sectional area of multifidus and psoas in patients with unilateral back pain: the relationship to pain and disability. Spine (Phila Pa 1976). 2004;29(22):E515–519.

    Article  PubMed  Google Scholar 

  30. Fortin M, Macedo LG. Multifidus and paraspinal muscle group cross-sectional areas of patients with low back pain and control patients: a systematic review with a focus on blinding. Phys Ther. 2013;93(7):873–88.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Danneels LA, Vanderstraeten GG, Cambier DC, Witvrouw EE, De Cuyper HJ. CT imaging of trunk muscles in chronic low back pain patients and healthy control subjects. Eur Spine J. 2000;9(4):266–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mannion AF, Kaser L, Weber E, Rhyner A, Dvorak J, Muntener M. Influence of age and duration of symptoms on fibre type distribution and size of the back muscles in chronic low back pain patients. Eur Spine J. 2000;9(4):273–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. James G, Klyne DM, Millecamps M, Stone LS, Hodges PW. ISSLS Prize in Basic science 2019: physical activity attenuates fibrotic alterations to the multifidus muscle associated with intervertebral disc degeneration. Eur Spine J. 2019;28(5):893–904.

    Article  CAS  PubMed  Google Scholar 

  34. Pan D, Zhang Z, Chen D, Huang Q, Sun T. Morphological alteration and TGF-beta1 expression in multifidus with lumbar disc herniation. Indian J Orthop. 2020;54(Suppl 1):141–9.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nielsen AR, Mounier R, Plomgaard P, Mortensen OH, Penkowa M, Speerschneider T, Pilegaard H, Pedersen BK. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J Physiol. 2007;584(Pt 1):305–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pecchi E, Priam S, Gosset M, Pigenet A, Sudre L, Laiguillon MC, Berenbaum F, Houard X. Induction of nerve growth factor expression and release by mechanical and inflammatory stimuli in chondrocytes: possible involvement in osteoarthritis pain. Arthritis Res Ther. 2014;16(1):R16.

    Article  PubMed  PubMed Central  Google Scholar 

  37. de Boer TN, van Spil WE, Huisman AM, Polak AA, Bijlsma JW, Lafeber FP, Mastbergen SC. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthritis Cartilage. 2012;20(8):846–53.

    Article  PubMed  Google Scholar 

  38. Klyne DM, Barbe MF, van den Hoorn W, Hodges PW, ISSLS PRIZE IN CLINICAL SCIENCE. 2018: longitudinal analysis of inflammatory, psychological, and sleep-related factors following an acute low back pain episode-the good, the bad, and the ugly. Eur Spine J 2018, 27(4):763–777.

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by National Key Research and Development Program of China (No. 2020YFC2004900).

Author information

Authors and Affiliations

  1. Department of Orthopaedics, Xuanwu Hospital Capital Medical University, Changchun Street 45, Xicheng District, 100032, Beijing, China

    Xiaolong Chen, Yongjin Li, Wei Wang, Peng Cui, Yu Wang & Shibao Lu

Authors
  1. Xiaolong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongjin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peng Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shibao Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Peng Cui and Yu Wang. The first draft of the manuscript was written by Xiaolong Chen, and all authors commented on previous versions of the manuscript. Yongjin Li and Wei Wang provided great comments during the revision process. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiaolong Chen or Shibao Lu.

Ethics declarations

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. The studies involving human participants were reviewed and approved by the Human Research Ethics Committee of Xuanwu Hospital Capital Medical University (CMUXW-2019012).

Consent to participate

Informed consent was obtained from all individual participants included in the study. All experiments were performed with the approval of Xuanwu Hospital Capital Medical University Human Research Ethics Committee where participants had consented for surgically discarded tissue to be used for research. All methods were carried out in accordance with relevant guideline and regulations. All experimental protocols were approved by the Human Research Ethics Committee of Xuanwu Hospital Capital Medical University.

Consent to publish

Not applicable.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Li, Y., Wang, W. et al. Correlation between inflammatory cytokine expression in paraspinal tissues and severity of disc degeneration in individuals with lumbar disc herniation. BMC Musculoskelet Disord 24, 193 (2023). https://doi.org/10.1186/s12891-023-06295-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12891-023-06295-z

Keywords

BMC Musculoskeletal Disorders

ISSN: 1471-2474

Contact us