Resistance Exercise Training and Amino Acid Leucine Supplementation in Frail Elderly Women

The Impact of Exercise Training and Leucine Supplementation in Frail Elderly Women With an Exploration Into Mechanistic Explanations

Frailty is a clinical entity associated with an increase in risk for disease and death and becomes more common as people age. Frailty has a strong relationship with the age-related loss of muscle and strength, termed sarcopenia. Sarcopenia and frailty are strongly associated with disability, especially in women. Adequate protein intake, the amino acid leucine, and resistance exercise training have been individually shown to increase muscle mass to varying degrees. However, no studies have investigated how a longer-term resistance exercise training program with leucine supplementation when protein intake is optimized could increase muscle mass in frail and pre-frail elderly women. In addition, this is the population that stands the most to gain from such an intervention.

The purpose of this study is to investigate the effects of the amino acid leucine added to resistance exercise training on muscle mass and physical performance in frail and pre-frail elderly women with adequate protein intake. We hypothesize that combining leucine in diet with an exercise program would be superior to exercise alone in stimulating muscle protein synthesis and phosphorylation status of muscle cellular key-regulatory proteins, leading to enhanced gains in muscle performance.

A total of 24 subjects will take part in this study, conducted at the McGill University Health Centre (MUHC) Royal Victoria Hospital and the Institut Universitaire de Gériatrie de Montréal (IUGM). All subjects will undergo adjustments to their diet to optimize protein intake and a resistance exercise training program. Half of the participants will receive a supplement of powdered leucine (an amino acid), and the other half of the participants will receive a placebo in the same powder form. Neither the participants nor the study investigators will know which participants are receiving the leucine nor which are receiving the placebo.

Each subjects participation in this study will involve 4 total visits: 2 initial screening visits followed by 2 two-day stays at the Centre for Innovative Medicine (CIM) of the MUHC-Royal Victoria Hospital. These two stays will be spaced by 12 weeks of the intervention (dietary adjustments, resistance exercise training, and the powdered supplement). The two stays each consist of a meal test to assess each subjects metabolic responses to a meal, and to obtain muscle biopsies necessary to measure the rate of protein accumulation in the muscle. Simple physical performance measurements will be taken before and at the completion of the intervention.

This study aims to better understand how the presence of aging affects the body's responses to resistance exercise and how leucine, one of the amino acids that make up proteins, may help build muscle. This in turn, could lead to defining combined diet and exercise strategies to prevent muscle loss often seen with aging.

Study Overview

• Status: Completed
• Conditions: Frail Elderly
• Intervention / Treatment: Dietary supplement: Leucine; Dietary supplement: Alanine

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3W 1W5
      • Institut Universitaire de Gériatrie de Montréal
    • Montreal, Quebec, Canada, H4A 3J1
      • Royal Victoria Hospital - Glen site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Mini Mental State Examination score > 24
• Time up and go test < 17 s
• Stable weight and diet
• No acute disease
• Body mass index (BMI) 20-35 kg/m^2
• Normal complete blood count (CBC), biochemistry, glycated hemoglobin (A1C), lipid profile, thyroid stimulating hormone (TSH)
• Non-diabetic (Oral Glucose Tolerance Test)
• Negative serology for hepatitis and human immunodeficiency virus (HIV)
• Normal chest X-Ray, electrocardiogram (ECG) and urine analysis
• Non-disabled
• Provide informed consent

Exclusion Criteria:

• Eating disorder,
• Food allergies affecting diet
• Substance abuse
• Active medical conditions including diabetes and any cancer other than skin within 5 years
• Serum creatinine > 110 umol/L, Hb < 110 g/L
• Medications known to interfere with the metabolic endpoint measurements: diuretics, beta-blockers, bronchodilators, non-steroidal anti-inflammatory drugs (NSAIDs), antianginals, antiarrythmics and steroids (other than topical)
• Disability

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Leucine; 2.5 g doses of leucine isolate three times per day (7.5 g total) of leucine, taken by mouth in powder form mixed with liquid for 12 consecutive weeks.	Dietary supplement: Leucine
Placebo Comparator: Alanine; 2.5 g doses of alanine isolate three times per day (7.5 g total) of alanine, taken by mouth in powder form mixed with liquid for 12 consecutive weeks.	Dietary supplement: Alanine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline in Fractional Synthesis Rate (FSR) at 12 weeks	Baseline and at 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Physical Performance at 12 weeks	Short Physical Performance Battery test, Timed-up-and-Go test 6 Minute Walk Test 1 repetition maximum Hand-grip strength	Baseline and at 12 weeks
Change from Baseline in Body Composition at 12 weeks	Dual energy X-ray absorptiometry	Baseline and at 12 weeks
Change from Baseline in Post-prandial responses at 12 weeks	Will measure excursion curves of glucose, insulin, branched chain amino acids, and amino acid profile	Baseline and at 12 weeks
Change from Baseline in Fasting levels at 12 weeks	Will measure fasting levels of insulin growth factor-1 (IGF-1), interleukin-6 (IL-6), cortisol, as well as resting metabolic rate	Baseline and at 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Quality of Life at 12 weeks	EuroQuol EQ-5D-5L™	Baseline and at 12 weeks
Change from Baseline in Mammalian target of rapamycin (mTOR) signalling proteins at 12 weeks	Quantity of the following proteins and their phosphorylation status: Protein kinase B (Akt) and phosphorylation on Ser473; Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and phosphorylation on Thr37/46; Ribosomal protein S6 kinase beta-1 (S6K1) and phosphorylation on Thr389; Ribosomal protein S6 (rpS6) and phosphorylation on Ser240/244; Proline-rich Akt substrate of 40 kilodaltons (PRAS40) and phosphorylation on Thr246; Forkhead box O3a (FoxO3a) and phosphorylation on Thr32	Baseline and at 12 weeks

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Investigators: Principal Investigator: José A Morais, MD, McGill University Health Centre/Research Institute of the McGill University Health Centre

Publications and helpful links

General Publications

• Jacob KJ, Sonjak V, Spendiff S, Hepple RT, Chevalier S, Perez A, Morais JA. Mitochondrial Content, but Not Function, Is Altered With a Multimodal Resistance Training Protocol and Adequate Protein Intake in Leucine-Supplemented Pre/Frail Women. Front Nutr. 2021 Jan 22;7:619216. doi: 10.3389/fnut.2020.619216. eCollection 2020.
• Jacob KJ, Chevalier S, Lamarche M, Morais JA. Leucine Supplementation Does Not Alter Insulin Sensitivity in Prefrail and Frail Older Women following a Resistance Training Protocol. J Nutr. 2019 Jun 1;149(6):959-967. doi: 10.1093/jn/nxz038.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): February 8, 2018
• Study Completion (Actual): December 17, 2018

Study Registration Dates

• First Submitted: July 26, 2013
• First Submitted That Met QC Criteria: August 12, 2013
• First Posted (Estimate): August 14, 2013

Study Record Updates

• Last Update Posted (Actual): March 8, 2019
• Last Update Submitted That Met QC Criteria: March 7, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Aging; Frailty; Resistance Exercise; Leucine
• Other Study ID Numbers: MUHC-H-5461