Lumbar Spine Muscle Degeneration Inhibits Rehabilitation-Induced Muscle Recovery

Sponsor
University of California, San Diego (Other)
Overall Status
Recruiting
CT.gov ID
NCT03442374
Collaborator
Balgrist University Hospital (Other), Spine Institute of San Diego (Spine Zone) (Other)
40
1
2
35
1.1

Study Details

Study Description

Brief Summary

Low back pain (LBP) is a complex condition that affects 65-85% of the population, and is the leading musculoskeletal condition contributing to disability in the United States. Disc herniation is the most common injury and 75% of individuals undergoing surgical and rehabilitative interventions for this condition experience suboptimal or poor outcomes. These patients demonstrate disability and deficits in functional capacity, including strength and endurance of the lumbar musculature. Muscle-specific changes in individuals with LBP include altered muscle volume, fatty infiltration and fibrosis, and fiber area and type. Importantly, these changes are insensitive to rehabilitation in patients with continued chronic or recurrent symptoms. While normal disuse-related atrophy in the presence of LBP is expected, more severe or chronic pathology, such as inflammation and fiber damage, may be inducing irreversible fiber degeneration and fatty/fibrotic tissue changes that impair muscle function and recovery. While the structural and adaptive capacities of healthy muscle are well understood, muscle recovery in the presence of pathology is less clear. To address this gap in knowledge, the purpose of this project is to compare structural, physiological, and adaptive responses of muscle in the presence of acute and chronic lumbar spine pathology. The central hypothesis is that chronic injury results in a state of muscle inflammation, atrophy, fibrosis, and muscle degeneration that is not responsive to exercise. The Investigators will identify which patients respond to exercise by examining muscle hypertrophic, fibrotic, inflammatory, and adipogenic gene expression profiles. Patients will be followed for six months post-operatively to measure muscle recovery and strength.

Condition or Disease Intervention/Treatment Phase
  • Other: Exercise
N/A

Detailed Description

AIM: To determine the effect of exercise on induction of muscle hypertrophic, fibrotic, inflammatory, and adipogenic pathways in patients with mild versus severe fatty infiltration of the multifidus muscle. Rationale. The objectives of this aim are to 1) measure molecular responses of muscle to a well-defined bout of pre-operative exercise, and 2) to determine if baseline morphological or exercise-induced molecular responses predict muscle structural recovery and functional gains up to 6 months post-operatively.

Design. This will be a longitudinal study of 40 patients with mild (< 20%) versus severe (> 50%) fatty infiltration. Non-exercise controls will also be important and the investigators intend to use a portion of biopsied tissue from other experiments as additional controls. Prior to surgery, patients will undergo clinical and MRI examinations. Additionally, patients will undergo an exercise bout 6 hours pre-operatively, and then immediately undergo a short MRI imaging protocol to measure exercise-induced perfusion changes (IVIM). Six hours after the exercise bout, the investigators will collect biopsies of the multifidus during surgery to characterize the hypertrophic, fibrotic, adipogenic, and inflammatory responses. For primary analyses, patient groups will be selected on the basis of severity of muscle fatty infiltration. Group ages and genders will be matched because the investigators know that baseline and exercise-induced gene expression varies with age. Surgical procedure and manipulation of the disc intraoperatively will be documented to account for the potential for disc and other surgery-specific effects on muscle structure. Six months post-operatively, repeated measures of muscle structure will be made via MRI. At 6, 12, and 24 weeks, strength (isokinetic dynamometer) and patient-specific function (questionnaire data) will be obtained as per standard protocol.

Methods:

Physical Examination: A physical therapist with spine injury experience will conduct the clinical exam. Age, gender and body mass index (BMI), duration of symptoms, anti-inflammatory drug use, active and passive range of motion, provocative neural tension tests (measuring joint range of motion [ROM]), strength and endurance as measured on an isokinetic dynamometer (MedX Holdings Inc.), neurovascular status, Oswestry Disability Index (81), Baecke Physical Activity Questionnaire (BPA), Fear Avoidance Beliefs Questionnaire (FABQ), and Pain Catastrophizing Scale (PCS) are important measures that capture both physical and psychosocial factors known to be related to LBP and will be collected at the clinical site. This screen will be used to confirm that discogenic symptoms are isolated to levels below L4, which allows us to use vastus lateralis as an internal control muscle biopsy.

Clinical MRI: Standard axial, sagittal oblique, and coronal oblique MR images of the spine will be collected on all patients who are scheduled for surgery. To identify disc injury severity (Pfirrmann grade), muscle fatty infiltration (Kjaer grade), and to confirm injury location, T1 and T2 non-fat suppressed or contrast-enhanced axial and sagittal MR images of the spine joint will be used.

Multimodal MRI: Imaging will be performed in a single session on a state-of-the-art 3T MRI system (GE MR750). The quantity and distribution of spine muscle volume, fat volume, and connective tissue volume will be performed from supine scans using high-resolution (1mm3) 3D FSPGR, IDEAL fat-water separation, and UTE pulse sequences, respectively using a 32-channel spine array coil. IVIM will be used to quantify regional muscle activation in response to an exercise bout.

Exercise protocol: Prior to surgery, patients will be subjected to a lumbar spine exercise protocol on a MedX Lumbar extension dynamometer with a pelvic restraint system allowing for isolation of lumbar spine muscles. The exercise protocol consists of 1 set of 20 repetitions (range 15-25 reps) at a rate of 5 seconds/repetitions with a starting weight of 60-80% of their computerized strength score. Patients will be instructed to target an exertion level of 7/10 on the Borg Rate of Perceived Exertion (RPE) scale within their available passive ROM range into flexion-extension.

Diet protocol: Importantly, the patients will remain NPO (no food or water) after the exercise bout but will have a standardized diet for 24 hours prior to the exercise bout and surgery, which mitigates the effects of diet on gene expression (137, 150-152). Evening meals will be standardized (1900h: 11 kcal/kg; 60% carbohydrate [CHO], 25% fat [FAT], 15% protein [PRO]; 2200h (3 kcal/kg; 95% CHO, 2% FAT, 3% PRO) because meal composition can acutely impact gene and protein expression.

Harvesting and storage of muscle biopsy: Muscle biopsies will be harvested within 6 hours of the exercise bout at their scheduled surgery time. Subjects will be excluded from the analysis if their biopsies are not harvested within 1 hour of the prescribed time point. Biopsies will be obtained with a standard biopsy clamp at the middle and deep margins of the multifidus muscle as noted in Aim #1 and immediately placed in RNAlater (Qiagen) for subsequent qPCR analysis or frozen in liquid nitrogen for protein abundance/phosphorylation measurements.

qPCR and western blotting: Gene expression and protein abundance will be measured by, qPCR and western blotting, respectively. Briefly, real-time PCR will be performed in a Bio-Rad CFX384 using customized plates (PrimePCR, Bio-Rad). Target gene expression will be calculated relative to values from 18S ribosomal subunit, as preliminary findings demonstrate it to be more stable than glyceraldehyde-3-phosphate dehydrogenase (GAPDH; data not presented). For genes in which we find a greater than 3-fold change in expression, western blotting will be used to assess protein abundance, as previously described.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
40 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Stratified by fatty infiltration severity (n=20/group x 2 groups + non exercise controls n=20)Stratified by fatty infiltration severity (n=20/group x 2 groups + non exercise controls n=20)
Masking:
Single (Outcomes Assessor)
Primary Purpose:
Basic Science
Official Title:
Lumbar Spine Muscle Degeneration Inhibits Rehabilitation-Induced Muscle
Actual Study Start Date :
Jul 1, 2019
Anticipated Primary Completion Date :
Jun 1, 2022
Anticipated Study Completion Date :
Jun 1, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Exercise

A single bout of moderate intensity lumbar extensor muscle exercise.

Other: Exercise
The exercise protocol consists of 1 set of 20 repetitions (range 15-25 reps) at a rate of 5 seconds/repetitions with a starting weight of 60-80% of their computerized strength score. Patients will be instructed to target an exertion level of 7/10 on the Borg Rate of Perceived Exertion (RPE) scale within their available passive ROM range into flexion-extension

No Intervention: Non-exercise

No exercise intervention.

Outcome Measures

Primary Outcome Measures

  1. Change in Multifidus Muscle Fatty Infiltration [6 months]

    (% fat at 6 months - % fat at baseline / % fat at baseline)

Secondary Outcome Measures

  1. Change in Oswestry Disability Index (ODI) [6 Months]

    Disability Questionnaire (10 questions, % scale is sum of 10 questions/50, higher score is worse), 6 months - baseline

  2. Change in Fear Avoidance Beliefs Questionnaire (FABQ) [6 months]

    Fear Avoidance Behaviors (sumo 16 items, 0-64 scale, higher score is worse), 6 months- baseline

  3. Change in Pain Catastrophizing Scale (PCS) [6 months]

    Pain behaviors questionnaire (sum of 13 items, 0-52 scale, higher score is worse), 6 months - baseline

  4. Change in Activated Muscle Volume (%) [After exercise (within 5 minutes)]

    (% muscle activation after exercise - % muscle activation at baseline / % muscle activation at baseline)

  5. Change in Pain (VAS) [6 months]

    Visual Analog Scale (0-100 mm scale), 6 months - baseline

  6. Change in Strength [6 months]

    MedEx dynamometer, Back Extensor Strength (Nm), 6 months - baseline

  7. MYHC3 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    Embryonic myosin heavy chain gene expression

  8. MHY3 protein abundance (ug/mg) [6 hours after a single exercise bout]

    Embryonic myosin heavy chain protein abundance

  9. MYOG gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    Myogenin gene expression

  10. MYOG protein abundance (ug/mg) [6 hours after a single exercise bout]

    Myogenin protein abundance

  11. PAX7 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    PAX7 gene expression

  12. PAX7 gene expression (ug/mg) [6 hours after a single exercise bout]

    PAX7 protein abundance

  13. ANKRD2 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    ANKRD2 gene expression

  14. ANKRD2 protein abundance (ug/mg) [6 hours after a single exercise bout]

    ANKRD2 protein abundance

  15. MTOR gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    MTOR gene expression

  16. MTOR protein abundance (ug/mg) [6 hours after a single exercise bout]

    MTOR protein abundance

  17. COL1A1 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    COL1A1 gene expression

  18. COL3A1 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    COL3A1 gene expression

  19. COL9A1 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    COL9A1 gene expression

  20. LOX gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    LOX gene expression

  21. CTGF gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    CTGF gene expression

  22. TGFB1 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    TGFB1 gene expression

  23. MMP1 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    MMP1 gene expression

  24. MMP3 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    MMP3 gene expression

  25. MMP9 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    MMP9 gene expression

  26. CEBPA gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    CEBPA gene expression

  27. FABP4 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    FABP4 gene expression

  28. PPARG gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    PPARG gene expression

  29. PPARD gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    PPARD gene expression

  30. LEP gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    LEP gene expression

  31. ADIPOQ gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    ADIPOQ gene expression

  32. CASP1 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    CASP1 gene expression

  33. CASP3 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    CASP3 gene expression

  34. TNFa gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    TNFa gene expression

  35. IL10 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    IL10 gene expression

  36. IL6 gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    IL6 gene expression

  37. IL1B gene expression (delta CT/delta CT) [6 hours after a single exercise bout]

    IL1B gene expression

  38. COL1A1 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    COL1A1 Protein abundance

  39. COL3A1 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    COL3A1 Protein abundance

  40. COL9A1 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    COL9A1 Protein abundance

  41. LOX Protein abundance (ug/mg) [6 hours after a single exercise bout]

    LOX Protein abundance

  42. CTGF Protein abundance (ug/mg) [6 hours after a single exercise bout]

    CTGF Protein abundance

  43. TGFB1 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    TGFB1 Protein abundance

  44. MMP1 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    MMP1 Protein abundance

  45. MMP3 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    MMP3 Protein abundance

  46. MMP9 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    MMP9 Protein abundance

  47. CEBPA Protein abundance (ug/mg) [6 hours after a single exercise bout]

    CEBPA Protein abundance

  48. FABP4 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    FABP4 Protein abundance

  49. PPARG Protein abundance (ug/mg) [6 hours after a single exercise bout]

    PPARG Protein abundance

  50. PPARD Protein abundance (ug/mg) [6 hours after a single exercise bout]

    PPARD Protein abundance

  51. LEP Protein abundance (ug/mg) [6 hours after a single exercise bout]

    LEP Protein abundance

  52. ADIPOQ Protein abundance (ug/mg) [6 hours after a single exercise bout]

    ADIPOQ Protein abundance

  53. CASP1 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    CASP1 Protein abundance

  54. CASP3 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    CASP3 Protein abundance

  55. TNFa Protein abundance (ug/mg) [6 hours after a single exercise bout]

    TNFa Protein abundance

  56. IL10 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    IL10 Protein abundance

  57. IL6 Protein abundance (ug/mg) [6 hours after a single exercise bout]

    IL6 Protein abundance

  58. IL1B Protein abundance (ug/mg) [6 hours after a single exercise bout]

    IL1B Protein abundance

  59. Change in Multifidus muscle volume (%) [baseline]

    Multifidus muscle volume (cc), (6 months - baseline/baseline)

Eligibility Criteria

Criteria

Ages Eligible for Study:
21 Years to 85 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Spine pathologies requiring un-instrumented surgery (i.e. laminectomy, laminoforaminotomy, or discectomy).

  • Age 21-85 years of age.

Exclusion Criteria:
  • History of lumbar spine surgery.

  • Patients requiring placement of instrumentation as part of the surgical procedure (i.e. fusion).

  • Diabetes.

  • Neuromuscular diseases.

Contacts and Locations

Locations

Site City State Country Postal Code
1 UC San Diego La Jolla California United States 92093

Sponsors and Collaborators

  • University of California, San Diego
  • Balgrist University Hospital
  • Spine Institute of San Diego (Spine Zone)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Samuel R. Ward, Professor and Vice Chair of Research, University of California, San Diego
ClinicalTrials.gov Identifier:
NCT03442374
Other Study ID Numbers:
  • HD088437
First Posted:
Feb 22, 2018
Last Update Posted:
May 4, 2022
Last Verified:
May 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Samuel R. Ward, Professor and Vice Chair of Research, University of California, San Diego
Additional relevant MeSH terms:

Study Results

No Results Posted as of May 4, 2022