Preserving Muscle Mass and Function in Bedridden Older Adults

The University of Texas Medical Branch, Galveston123 enrolled

Overview

The investigators propose that low-intensity exercise and supplementing daily meals with leucine or whey will independently and synergistically reduce the deleterious effects of inactivity on skeletal muscle and facilitate recovery during rehabilitation.

The loss of muscle mass and function in older adults during bed rest is facilitated by defects in the regulation of muscle protein metabolism, including an impaired ability to mount an anabolic response to a mixed nutrient meal. The investigators propose that low-intensity exercise and supplementing daily meals with leucine or whey will independently and synergistically reduce the deleterious effects of inactivity on skeletal muscle and facilitate recovery during rehabilitation. Metabolic measures will include: a) nutrient and exercise-specific markers of translation initiation; b) skeletal muscle protein synthesis; and c) a novel breath test of glucose tolerance. Morphologic and functional measures will include: a) muscle mass and body composition; b) muscle strength and function; and c) motor activation. The investigators will test the following hypotheses in older men and women (65-80 years) during 7 days of bed rest followed by 7 days of inpatient rehabilitation: 1. Inactivity-induced metabolic dysregulation will blunt the anabolic response to meals, facilitating a loss of lean muscle mass, glucose tolerance and functional capacity that is partially restored during rehabilitation. 2. Supplementing daily meals with leucine or whey will maintain nutrient-stimulated translation initiation and preserve the anabolic response to meal ingestion. This will partially preserve lean muscle mass and function during bed rest and facilitate the recovery of functional and metabolic capacity during rehabilitation. 3. Daily low-intensity exercise will preserve motor unit activation, stimulate the exercise-regulated signaling pathway and normalize the anabolic response to meal ingestion. This will partially preserve glucose tolerance, lean muscle mass and function during bed rest and facilitate rehabilitation. This translational project will provide mechanistic and practical insight into strategies to reduce the negative consequences of physical inactivity and promote rehabilitation in aging muscle. Our novel, minimally invasive and clinically interventions have direct application for older hospitalized patients at risk of accelerated muscle loss and diminished functional capacity.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

123

Conditions

Bed Rest

Interventions

LeucineDIETARY_SUPPLEMENT

ExerciseBEHAVIORAL

Whey proteinDIETARY_SUPPLEMENT

Eligibility

Sex: ALLMin age: 60 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age between 60-80 2. Ability to sign informed consent 3. Ability to pass a mini-mental status exam 4. Free-living, prior to admission Exclusion Criteria: 1. Subjects with cardiac abnormalities considered exclusionary by the study physicians 2. Subjects with uncontrolled metabolic disease 3. A glomerular filtration rate (GRF) \<65 mL/min/1.73m2 or evidence of kidney disease or failure 4. Subjects with vascular disease or risk factors of peripheral atherosclerosis. (e.g., uncontrolled hypertension, obesity, diabetes, hypercholesterolemia \> 250 mg/dl, claudication or evidence of venous or arterial insufficiency upon palpitation of femoral, popliteal and pedal arteries. 5. Any history of hypo- or hyper-coagulation disorders. (e.g., Coumadin use or history of deep vein thrombosis (DVT) or PE). 6. Subjects with chronically elevated systolic pressure \>170 or a diastolic blood pressure \> 100. 7. Subjects with implanted electronic devices (e.g., pacemakers, electronic infusion pumps, stimulators) 8. Subjects with recently (6 months) treated cancer other than basal cell carcinoma 9. Any subject currently on a weight-loss diet or a body mass index \> 30 kg/m2. 10. A history of \> 20 pack per year smoking and/or inability to abstain from smoking for duration of study 11. Any subject that is HIV-seropositive or has active hepatitis 12. Recent anabolic or corticosteroids use (within 3 months). 13. Subjects with hemoglobin or hematocrit lower than accepted lab values. 14. Dementia, agitation/aggression disorder 15. History of stroke with motor disability 16. A recent history (\<12 months) of GI bleed 17. Any other condition or event considered exclusionary by the PI and faculty physician.

Locations (1)

Unversity of Texas Medical Branch

Galveston, Texas, United States

Outcomes

Primary Outcomes

Change in lean leg mass from baseline following seven days of bed rest and seven days of rehabilitation. (Morphologic primary measure)

The lower body musculature is primarily affected by physical inactivity (19). Lean leg mass will be determined by segmental dual energy x-ray absorptiometry (iDXA:General Electric, Lunar, Madison, WI). The whole body scan will be divided in sub-regions for analysis.

Time frame: Study day 3, 11, 18, 39

Change in stair climbing power test from baseline following seven days of bed rest and seven days of rehabilitation (Primary functional outcome)

Loss of leg muscle power occurs during prolonged bed rest (-14.4+4 % in 10 days)and is a key factor contributing to impaired mobility, balance and functional capacity. Climbing power will be calculated as the time to ascend 10 steps \[Power = (Distance/Time) x Body Weight\].

Time frame: Study day 3, 11, 18, 39

Change in mixed muscle fractional synthesis rate (FSR) from baseline following seven days of bed rest and seven days of rehabilitation (Primary metabolic outcome)

Mixed muscle FSR will be calculated by measuring the direct incorporation of a stable isotope of phenylalanine into protein using the precursor-product model.

Time frame: Study day 4, 11, 18

Secondary Outcomes

Change in cell signaling from baseline following seven days of bed rest and seven days of rehabilitation (Secondary metabolic measure)

We will examine protein content and phosphorylation status of key exercise and nutrient sensitive signaling proteins in the mammalian target of rapamycin.

Time frame: Study day 4, 11, 18

Change in hormones and cytokines from baseline following seven days of bed rest and seven days of rehabilitation (Secondary Metabolic measure)

Analysis will be performed on existing blood and tissue samples collected for primary metabolic analysis. Serum concentrations of insulin, testosterone, and hsCRP will be analyzed. Serum and muscle tissue concentrations of cytokines and biomarkers, including tumor necrosis factor-alpha (TNF-a), interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-γ) will also be assessed.

Data from ClinicalTrials.gov

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