Lumbar Spine Muscle Degeneration Inhibits Rehabilitation-Induced Muscle
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 62
- Locations
- 2
- Primary Endpoint
- Change in Multifidus Muscle Fatty Infiltration
Study Overview
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.
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- Masking
- Single (Outcomes Assessor)
Eligibility Criteria
- Ages
- 21 Years to 85 Years (Adult, Older Adult)
- Sex
- 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.
Outcomes
Primary Outcomes
Change in Multifidus Muscle Fatty Infiltration
Time Frame: 6 months
(% fat at 6 months - % fat at baseline / % fat at baseline)
Secondary Outcomes
- PPARD Protein abundance (ug/mg)(6 hours after a single exercise bout)
- Change in Fear Avoidance Beliefs Questionnaire (FABQ)(6 months)
- Change in Oswestry Disability Index (ODI)(6 Months)
- MYOG gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- ANKRD2 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- COL1A1 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- CTGF gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- CEBPA gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- LEP gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- CASP3 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- IL1B gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- LOX Protein abundance (ug/mg)(6 hours after a single exercise bout)
- MMP1 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- ADIPOQ Protein abundance (ug/mg)(6 hours after a single exercise bout)
- Change in Pain (VAS)(6 months)
- MHY3 protein abundance (ug/mg)(6 hours after a single exercise bout)
- PAX7 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- PPARD gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- Change in Pain Catastrophizing Scale (PCS)(6 months)
- Change in Strength(6 months)
- MYHC3 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- PAX7 gene expression (ug/mg)(6 hours after a single exercise bout)
- MYOG protein abundance (ug/mg)(6 hours after a single exercise bout)
- COL3A1 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- LOX gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- ADIPOQ gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- COL1A1 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- CASP1 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- CASP3 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- IL6 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- IL1B Protein abundance (ug/mg)(6 hours after a single exercise bout)
- TNFa Protein abundance (ug/mg)(6 hours after a single exercise bout)
- IL10 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- FABP4 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- CASP1 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- Change in Multifidus muscle volume (%)(baseline)
- ANKRD2 protein abundance (ug/mg)(6 hours after a single exercise bout)
- COL9A1 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- TGFB1 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- MMP1 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- MMP3 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- IL10 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- COL9A1 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- TGFB1 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- LEP Protein abundance (ug/mg)(6 hours after a single exercise bout)
- MTOR gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- MTOR protein abundance (ug/mg)(6 hours after a single exercise bout)
- MMP9 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- PPARG gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- TNFa gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- IL6 gene expression (delta CT/delta CT)(6 hours after a single exercise bout)
- COL3A1 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- CTGF Protein abundance (ug/mg)(6 hours after a single exercise bout)
- MMP3 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- MMP9 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- CEBPA Protein abundance (ug/mg)(6 hours after a single exercise bout)
- FABP4 Protein abundance (ug/mg)(6 hours after a single exercise bout)
- PPARG Protein abundance (ug/mg)(6 hours after a single exercise bout)
- Change in Activated Muscle Volume (%)(After exercise (within 5 minutes))
Investigators
Samuel R. Ward
Professor and Vice Chair of Research
University of California, San Diego