Clinical trial NCT06228742: Molecular Mechanisms Underlying Anabolic Resistance to Protein Intake During Muscle Disuse
Official title: Molecular Regulation of Skeletal Muscle Anabolic Resistance to Dietary Protein in Response to Injury-mediated Muscle Disuse
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Atrophy, Disuse
Muscle Atrophy
Muscular Disorders, Atrophic
Disuse Atrophy
Disuse Atrophy Muscle of Thigh
Lead sponsor: United States Army Research Institute of Environmental Medicine
Sponsor class: FED
First posted: 2024-01-29
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 39
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single leg immobilization model consisting of one leg randomly assigned to immobilization with a knee brace and the other leg remaining active and non-immobilized, for 5 days.
Primary purpose: BASIC_SCIENCE

Brief summary: This study will characterize intramuscular molecular mechanisms underlying anabolic resistance to protein ingestion during muscle disuse. Adults (n=12) will be studied using a unilateral leg immobilization model in which one leg will be randomly assigned to immobilization and the contralateral, active leg used as a within-subjects control. Immobilization will be implemented for five days using a rigid knee brace, during which time participants will ambulate using crutches. Integrated ribonucleic acid (RNA) synthesis will be determined during immobilization in the immobilized and non-immobilized legs using ingested deuterium oxide, salivary and blood sampling, and muscle biopsies. Immediately after immobilization, muscle biopsies will be collected before and 90 mins after consuming 25 g of whey protein from the immobilized and non-immobilized legs to characterize the intramuscular molecular response to protein feeding. Serial blood samples will be collected during that time to characterize the circulating metabolic response to protein ingestion. Knowledge generated from this effort will inform the development of targeted interventions for mitigating anabolic resistance to protein ingestion that develops during periods of muscle disuse.

Detailed description: Warfighters that sustain musculoskeletal injuries often experience decreased muscle loading and activation post-injury (i.e., muscle disuse) that results in a rapid loss of muscle mass and function. Loss of muscle under these conditions is attributed to a persistent negative net muscle protein balance (muscle protein synthesis \[MPS\] \< muscle protein breakdown \[MPB\]) that results, in part, from a blunting of MPS in the postprandial state. Nutritional interventions that optimize postprandial MPS have been suggested as countermeasures for this "anabolic resistance" that develops during disuse to preserve muscle mass and accelerate return to duty. However, a poor understanding of mechanisms underlying anabolic resistance during disuse has made it difficult to determine an optimal nutritional intervention. The current study will address this knowledge gap directly by characterizing intramuscular molecular mechanisms underlying anabolic resistance to protein ingestion during muscle disuse. Healthy, recreationally active men and women (n=12) will be studied using a within-subjects, unilateral design. After completing baseline measures of height, weight, and body composition, participants will begin a 3-day run-in phase where they will receive diet instructions (no food provided). Muscle disuse will then be implemented for 5 days using a unilateral leg immobilization model with one leg randomly assigned to immobilization and the contralateral, active leg used as a within-subjects control. Immobilization will be implemented using a rigid knee brace, and participants will ambulate using crutches. Diets will be standardized during the immobilization phase (1.0 g protein/kg/d, 30% of energy intake from fat, and the remaining calories from carbohydrate). Integrated ribonucleic acid (RNA) synthesis will be determined during immobilization in the immobilized and non-immobilized legs using ingested deuterium oxide, salivary and blood sampling, and muscle biopsies. Immediately after immobilization, muscle biopsies will be collected before and 90 mins after consuming 25 g of whey protein from the immobilized and non-immobilized legs to characterize the intramuscular molecular response to protein feeding. Serial blood samples will be collected during that time to characterize the circulating metabolic response to protein ingestion. Knowledge generated from this effort will inform the development of targeted interventions for mitigating anabolic resistance to protein ingestion that develops during periods of muscle disuse.

Eligibility criteria: Inclusion Criteria:

* Men and women aged 18-39 years.
* Body mass index (BMI) between 18.5-30 kg/m2
* Healthy without evidence of chronic illness (e.g., diabetes, cardiovascular disease, Crohn's disease) or musculoskeletal injury as determined by the USARIEM Office of Medical Oversight (OMSO) or home duty station medical support.
* Routinely participate in aerobic and/or resistance exercise at least 2 days per week.
* Willing to refrain from alcohol, smoking, smokeless nicotine products (includes e-cigarettes, vaping, chewing tobacco), caffeine, and dietary supplements (i.e., vitamin D, probiotics) during the run-in diet, immobilization phase, and final testing day of the study.
* Supervisor approval for federal civilian employees and non-human research volunteer (HRV) active-duty military personnel stationed at Natick Soldier System Center (NSSC).
* Biological females must have normal menstrual cycles between 26-32 days in duration; 5 menstrual cycles within the past 6 months; or on continuous hormonal contraception (i.e., intrauteraine device (IUD) or oral contraceptives without placebo).

Exclusion Criteria:

* Musculoskeletal injuries that may interfere with the safe use of crutches.
* Personal or family history of thrombosis, or prior diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE).
* Metabolic or cardiovascular abnormalities, gastrointestinal disorders, neuromuscular disorders, lower-limb amputation, or muscle/bone wasting disorders (e.g., diabetes, cardiovascular disease, Crohn's disease, etc.).
* Significantly abnormal blood clotting as determined by OMSO or home duty station medical support.
* Allergy to lidocaine (or similar local anesthetic)
* Present condition of alcoholism, anabolic steroid use, or other substance abuse issues as determined by OMSO or home duty station medical support.
* Blood donation within 8-wk of beginning the study.
* Pregnant, trying to become pregnant, and/or breastfeeding (results of urine pregnancy test and self-report for breastfeeding will be obtained before body composition testing).
* Unwilling or unable to consume study diets or foods provided due to personal preference and/or food allergies.
* Unwilling or unable to adhere to study physical restrictions (i.e., no structured physical activity or recreational activity beyond activities of daily living) 24 hours before and during immobilization, and the final testing day.
* Unwilling or unable to keep the knee brace on and walk with crutches during the immobilization phase.

Primary outcomes:
measure: Integrated ribonucleic acid (RNA) synthesis
timeFrame: 5 days
measure: Intramuscular protein signaling response to protein ingestion
timeFrame: 90 minutes
Secondary outcomes:
Other outcomes:
Locations:
city: Natick
country: United States
facility: US Army Research Institute of Environmental Medicine
state: Massachusetts
Study officials:
affiliation: US Army Research Institute of Environmental Medicine
name: Emily E Howard, PhD
role: PRINCIPAL_INVESTIGATOR
References: