Imaging Skeletal Muscle Mitochondrial OXPHOS Activity In Acute Lymphoblastic Leukemia Survivors
Summary
The participants are being asked to take part in this trial, because the participant is a survivor of childhood cancer or agreed to be part of a volunteer group to understand the relation between cancer and cancer treatment and muscle weakness in survivors of Acute Lymphoblastic Leukemia (ALL). ALL is cancer of the blood and bone marrow. Primary Objective • To compare muscle mtOXPHOS activity and satellite cell content among ALL survivors and controls. Secondary Objective * To evaluate the association between muscle mtOXPHOS, muscle satellite cell content and physical performance in ALL survivors. * To evaluate the association of muscle morphology and epigenetics with muscle mtOXPHOS in ALL survivors.
Detailed description
This study hypothesizes that sarcopenia (low lean mass and muscle weakness), the central components of frailty, result from cancer- and or treatment-related impairment of cellular function within skeletal myocytes. Impaired mitochondrial oxidative phosphorylation (mtOXPHOS) is a hallmark of aging and implicated in skeletal muscle (muscle) weakness and lowered physical performance with normal aging. There is a lack of understanding of how the dysfunctional mitochondrial capacity affects the individual muscle groups in the lower extremities of the survivors. This pilot study will explore the feasibility of non-invasive metabolic imaging to measure the major muscle groups in the calf muscle mtOXPHOS in childhood survivors of Acute Lymphoblastic Leukemia (ALL) in SJLIFE cohort by incorporating magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in survivors and age/sex-matched healthy volunteers (Controls). Control participants will be recruited from SJLIFE control cohort and may be recruited from new SJLIFE controls; The MRI/MRS findings will be correlated with clinically ascertained muscle phenotype; and will explore and describe differences in muscle morphology, epigenetics, mtDNA-CN between survivors and controls using peripheral blood and muscle biopsies, and their association with MRI/MRS findings. Survivor and Control participants will be asked to have two MRI sessions; a physical function, and a muscle ultrasound assessment done during SJLIFE Human Performance Lab (HPL). Participants will be asked to give a peripheral blood sample and muscle sample. MR imaging will be performed in two appointments.
Arms & interventions
- Diagnostic TestMagnetic Resonance Imaging
Non-invasive MRI will be used to measure the major muscle groups in the calf muscle mtOXPHOS in childhood survivors of Acute Lymphoblastic Leukemia (ALL) in SJLIFE cohort and community controls and measure how muscle mitochondria produce energy to function.
- Diagnostic TestMagnetic Resonance Spectroscopy
Non-invasive MRS will be used to measure the major muscle groups in the calf muscle mtOXPHOS in childhood survivors of Acute Lymphoblastic Leukemia (ALL) in SJLIFE cohort and community controls and measure how muscle mitochondria produce energy to function.
- OtherPhysical function assessment
As part of the SJLIFE visit in the Human Performance Lab, the participant's physical health will be assessed by testing muscle strength, physical function, and lean muscle mass.
- OtherPeripheral blood sample
Peripheral blood sample will be used to evaluate muscle morphology, mitochondrial health and epigenetic differences in the muscles of survivors and age/sex-matched community controls.
- OtherSkeletal muscle biopsy
Muscle biopsy will be used to evaluate muscle morphology, mitochondrial health and epigenetic differences in muscles of survivors and age/sex-matched community controls.
- Diagnostic TestMuscle Ultrasound
Bilateral quadriceps and calf muscle ultrasound will be used to measure muscle volume by calculating the cross-sectional area using the Cavalieri method.
Outcome measures
Primary
To explore feasibility of MRI/MRS to measure OXPHOS capacity
Multimodal MR imaging will be performed in two appointments. The first appointment will consist of Part 1 (approximately 1 hour) and Part 2 (approximately 30 minutes). There will be a 5-10 minute break between the two parts. The second appointment will consist of Part 1 (approximately 1 hour).
Time frame: Baseline
To explore feasibility of 31P-MRS to measure OXPHOS capacity
This will be performed with a 7-cm diameter 1H/31P dual-tuned surface/volume coil using an unlocalized free induction decay (FID) sequence: number of points = 512, averages = 2-5, and TR = 2.4-5 seconds, with 4 dummy scans. TPCr is determined by fitting the signal intensity of PCr following plantar flexion exercise to a mono-exponential function. Additionally, we will acquire a steady state 31P-MR spectra for phosphorylated metabolite quantification (sec).
Time frame: Baseline
To explore feasibility of 1H-MRS to measure OXPHOS capacity
This will be performed on a Siemens 3T scanner using Point RESolved Spectroscopy (PRESS) 31 sequence. A water-suppressed 1H MR spectrum will be acquired from a voxel positioned in gastrocnemius and soleus muscles. 1H MRS data will be processed using LCModel providing the metabolite levels (mM).
Time frame: Baseline
To explore feasibility of CrCEST MRI to measure OXPHOS capacity
We will perform CrCEST MRI to map calf muscle Cr recovery kinetics (TCrCEST) following plantar flexion exercise (sec).
Time frame: Baseline
To explore feasibility of Fat Fraction MRI to measure OXPHOS capacity
We will perform Dixon MRI to quantify intramuscular fat fraction (IFF %) in the calf.
Time frame: Baseline
To explore feasibility of Muscle Ultrasound to measure OXPHOS capacity
Participants will lay supine with legs fully extended with their ankles stabilized in neutral. Customized templates will be strapped on the thigh and consist of five to eight 2-cm slices with a 1-cm gap between slices. Using transmission gel, a continuous, single view will be measured by transversely moving the probe across the thigh in approximately four seconds to acquire images of the rectus femoris (RF) and the vastus lateralis (VL), ensuring minimal pressure is applied to the skin to avoid muscle compression. Bilateral calf muscle CSA will be assessed in the same manner.
Time frame: Baseline
To explore feasibility of Muscle Biopsy to measure OXPHOS capacity
A vacuum-assisted biopsy device and ultrasound guidance will be used to obtain skeletal muscle samples. The procedure is performed under local anesthesia with the patient in supine position. The needle will be inserted into the vastus lateralis, accessed through a 2-3 mm incision, under local anesthesia. When the needle is removed, a small section of muscle will remain with the needle. Two samples will be obtained during the procedure. One sample will be analyzed for satellite cell content and morphology. The second sample will be analyzed for mtDNA-CN and epigenetic profile.
Time frame: Baseline
To explore feasibility of mtDNA-CN to measure OXPHOS capacity
Peripheral blood samples will be drawn and analyzed for mtDNA-CN, metabolic and epigenetic profile and compared to the muscle sample.
Time frame: Baseline
Secondary
Evaluate muscle strength to measure physical performance
Time frame: Baseline
Evaluate physical function to measure physical performance
Time frame: Baseline
Eligibility criteria
Study locations (1)
St. Jude Children's Research Hospital
Memphis, Tennessee, 38105