Lumbar Spine Muscle Degeneration Inhibits Rehabilitation-Induced Muscle Recovery
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Back Pain, Back Pain |
| Therapuetic Areas: | Musculoskeletal |
| Healthy: | No |
| Age Range: | 21 - 85 |
| Updated: | 2/24/2018 |
| Start Date: | July 2018 |
| End Date: | June 2022 |
| Contact: | Samuel Ward, PT, PhD |
| Email: | srward@ucsd.edu |
| Phone: | (858)534-4918 |
Lumbar Spine Muscle Degeneration Inhibits Rehabilitation-Induced Muscle
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.
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.
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.
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.
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.
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