Cancer Cachexia, Vitamin D Deficiency
Conditions
Keywords
vitamin D, muscle, metabolism, cancer cachexia
Brief summary
The proposed study is aimed at examining mitochondrial function as a potential target of action of vitamin D on muscle metabolism, size, and strength in preventing the progression of cachexia. This is the first clinical trial designed to understand the effects of vitamin D on muscle metabolic dynamics driving dysfunction in cachectic muscle. Our preliminary data suggest that vitamin D promotes lipid partitioning and muscle metabolic function, which the investigators hypothesize, will mitigate cachexia via improved muscle health and quality that translates into reduced fatigue, and improved patient resilience to multimodal cancer therapy.
Detailed description
Vitamin D repletion is linked to improved muscle mitochondrial function, lipid deposition and preservation; however, while vitamin D insufficiency is common in cancer, the mechanistic effects of vitamin D on muscle metabolic health in cancer patients have not been studied. This is important to address because cancer cachexia is characterized by marked muscle wasting, anabolic resistance, ectopic fat infiltration, mitochondrial dysfunction and contributes to decreased survival. With novel strategies to address this knowledge gap, the investigators will use a combination of advanced metabolic analytical approaches with complementary model systems in cell culture and human subjects to understand the biochemical and physiological mechanisms underlying cancer cachexia in relation to the role of vitamin D in conjunction with resistance exercise (RE). By combining analyses of muscle size and local tissue hemodynamics in vivo, metabolomics analyses of muscle tissue and isolated mitochondria, and changes in anabolic cell signaling, lipid metabolism and oxidative capacity of primary muscle cells in vitro, the investigators will identify mechanisms underlying muscle response to vitamin D repletion. Our previous findings, together with data that exercise improves muscle vitamin D storage and retrieval, suggest that vitamin D repletion synergizes with RE to improve muscle metabolic function and protein synthesis. Our overall objective is to examine mitochondrial function and anabolic resistance as potential targets of action of vitamin D on muscle metabolism, size and strength in preventing the progression of cachexia. The aims of this study are to: 1) non-invasively quantify lipid redistribution, local muscle tissue metabolism and muscle mass and strength of cancer patients before and after 12 weeks of double blinded vitamin D repletion with exercise and protein supplementation (VitD) compared to exercise and protein supplementation only (Ctl); 2) determine differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemius from VitD compared to Ctl; and 3) identify mechanisms whereby vitamin D and exercise regulate muscle anabolic signaling and mitochondrial activity in primary human myotube cultures. Our central hypothesis is that vitamin D promotes muscle lipid availability for β-oxidation in response to exercise, thereby preventing lipotoxicity in the muscle and potentially improving anabolic sensitivity in muscle during cancer cachexia. The impact of this project, the first nutrition and exercise study designed as an inexpensive intervention, is to understand the effect of vitamin D on the metabolic and anabolic dynamics which underpin dysfunction in cachectic muscle. If vitamin D promotes lipid partitioning, muscle metabolic function and/or anabolic sensitivity, these adaptations will ultimately improve cancer therapy by combating cancer cachexia. Further, diffuse optical spectroscopy techniques have the potential to identify the minimum effective intervention dose for optimizing metabolic health leading to more practical and individualized lifestyle prescriptions to reduce health care costs.
Interventions
DIETARY_SUPPLEMENTVitamin D
5,000IU vitamin D given daily for 12 weeks
DIETARY_SUPPLEMENTPlacebo
Placebo capsules given daily for 12 weeks
Sponsors
David Travis Thomas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
All subjects receive exercise and protein supplementation. Participants, Investigators, Care Providers, and outcome assessors will be blinded to vitamin D vs. placebo capsule allocation
Intervention model description
Prospective, double-blinded randomized controlled clinical trial
Eligibility
Sex/Gender
ALL
Age
45 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Patients must have histologically or cytologically confirmed stage II-IV lung cancer and be planned for definitive non-surgical therapy. Patients may have a history of prior malignancy. Mild cancer cachexia, defined by the miniCASCO score of 0-25 points Vitamin D insufficiency, defined as 25(OH)D \< 32 ng/ml Aged 45 to 75 years. Stratified randomization by age ECOG performance status ≤ 2 (see Appendix A). Life expectancy of greater than 3 months Patients must have normal renal and liver function as defined below: AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. Able to swallow thin liquids No uncontrolled illness including, but not limited to, any of the following: * Ongoing or active serious infection * Symptomatic congestive heart failure * Unstable angina pectoris * Uncontrolled cardiac arrhythmia * Uncontrolled hypertension * Psychiatric illness or social situation that would preclude compliance with study requirements Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients with untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with treated brain metastasis are eligible for this trial, providing they have completed treatment at least one day prior to registration. History of allergic reactions to whey or milk proteins. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with a history of calcium oxalate nephrolithiasis are excluded. Patients with a significant history of malabsorption (e.g. celiac sprue, short bowel syndrome, IBD or other, as determined by the treating physician) are excluded. Patients will not be eligible if actively receiving treatment for vitamin D deficiency and have had recent (3 month) history of vitamin D supplementation (\>1000 IU) or calcium supplementation (\>800mg). The following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Muscle Strength | Change between Week 0, Week 6, Week 12 | Maximal voluntary contractions and 1-Repetition Maximum will be aggregated to to provide a comprehensive assessment of muscle strength |
| Non-invasive quantification of muscle lipid distribution | Change between Week 0 and Week 12 | MRI/MRS |
| Local muscle oxygen consumption | Change between Week 0 and Week 12 | Near Infrared Spectroscopy + Diffuse Correlation Spectroscopy measures will be combined to assess changes in local muscle tissue oxygen consumption (VO2 measure) |
| Muscle Mass | Change between Week 0 and Week 12 | MRI |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mitochondrial Function in Muscle Fibers in Fresh Muscle Fibers ex vivo | Experiments will be conducted from tissue collected at week 12 study biopsy | Determine the differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemius from VitD compared to Ctl by measure live tissue oxygen consumption rate. Respiration measures will be combined to assess mitochondrial function Mitochondrial respiration will be measured by the XF96 Seahorse extracellular flux analyzer |
| Stable Isotope-Resolved Metabolomics to describe Fatty Acid Metabolism in relationship to other fuel substrates in Fresh Muscle Fibers ex vivo | Experiments will be conducted from live tissue collected at week 12 study biopsy | Determine the relative importance of vitamin D on lipid, amino acid and energy metabolism involving glucose, glutamine, and β-oxidation in intact muscle fibers. We will culture with 13C8-octanoate, 13C6-glucose, or 13C5-Gln and measure metabolite isotopomer distributions to accomplish this goal. |
| Utilize cell culture experimentation to understand anabolic signaling in response to vitamin D with or without fiber stretch. | Experiments will be conducted from tissue collected at week 12 study biopsy | Identify mechanisms whereby vitamin D and RE regulate anabolic signaling in primary human myotube cultures. Changes in signaling pathways associated with hypertrophy, including Akt, mTOR, MAPK, and AMPK, will be measured by phospho-western blot to determine response to calcitriol, palmitate, and stretch treatment in myotubes. |
| Utilize cell culture experimentation to measure mitochondrial activity in response to vitamin D with or without fiber stretch. | Experiments will be conducted from tissue collected at week 12 study biopsy | To understand how vitamin D and RE regulate mitochondrial activity in primary human myotube cultures, the investigators will measure extracellular acidification rate (ECAR) in response to calcitriol supplementation. This will be assessed through the addition of CPT-1 inhibitor etomoxir (40 µM) and the ATP-synthase inhibitor oligomycin |
Countries
United States
Outcome results
None listed