Identifying Therapeutic Targets of Accelerated Sarcopenia

The proposed research is designed to identify the mechanisms that can accelerate loss of muscle size, strength and physical function in type 2 diabetes and with hospitalization in older persons. About ⅓ of older Americans have type 2 diabetes, and about ⅓ of the hospitalizations in the USA involve persons older than 65 year of age. The proposed research is relevant to the part of NIH's mission that pertains to development of the fundamental knowledge that will improve health and reduce the burdens of disability, because this work will provide the fundamental evidence to identify new targets for the development of innovative treatments to slow down muscle loss and disability in our aging society.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Sarcopenia; Aging
• Intervention / Treatment: Behavioral: Resistance exercise training; Behavioral: Bed rest; Behavioral: Intensive physical therapy

Detailed Description

Sarcopenia is a major contributor to frailty and increases the risk of falls, physical dependence, disability and mortality in older adults. It advances slowly with healthy aging. However, diseases or other insults and injuries can accelerate sarcopenia and lead to catastrophic declines in mobility and independence. For example, chronic diseases such as Type 2 Diabetes Mellitus (T2DM) are associated with accelerated loss of muscle mass and function in seniors; hospitalization with bed rest inactivity acutely accelerates sarcopenia. What it is not known is how concurrent diseases, inactivity or other insults and injuries accelerate sarcopenia in older adults. This knowledge gap hinders the development of innovative, targeted treatments for this disabling condition. The objective of this research is to examine the basic mechanisms that underlie accelerated sarcopenia in older adults and identify potential targets for interventions. The central hypothesis is that a global and fundamental mechanism of acute or chronic acceleration of sarcopenia is a reduction in skeletal muscle amino acid transport, which decreases muscle protein anabolism, and can be reversed by activation of the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling with a non-amino acid stimulus, such as exercise. Amino acid transport is an active process that controls intracellular amino acid availability and the activation of protein synthesis in skeletal muscle. It is regulated by amino acid concentrations and non-amino acid stimuli that activate mTORC1 signaling, such as resistance exercise and insulin.The central hypothesis will be tested with the following specific aims: 1) Determine the effect of T2DM on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 2) Determine the effect of short-term bed rest inactivity on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 3) Determine the effect of resistance exercise on the sensitivity of amino acid transport to dietary amino acids in acute and chronic accelerated sarcopenia induced by inactivity or T2DM. Amino acid transport and protein metabolism in muscle will be measured using integrative molecular, imaging and stable isotope methodologies, identifying specific upstream regulators involved in the anabolic resistance of accelerated sarcopenia that can be targeted with novel treatments to reduce sarcopenia and improve independence in older adults.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Texas
    • Galveston, Texas, United States, 77550
      • Sealy Center on Aging, University of Texas Medical Branch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Body mass index: <40 kg/sq meter
• Score ≥26 on the 30-item Mini Mental State Examination
• Stable body weight for at least 3 months
• Non-diabetic or with Type 2 Diabetes Mellitus

Exclusion Criteria:

• Pre-diabetes per American Diabetes Association criteria
• Insulin therapy, significant diabetic complications, or A1c>8%
• Impairment in Activities of Daily Living
• >2 falls/year
• weight loss >5% in the past 6 months
• Exercise training (≥2 sessions/week) or ≥10,000 steps/day
• Significant cardiovascular, liver, renal, blood, or respiratory disease
• Active cancer or infection
• Recent (within 3 months) treatment with anabolic steroids, systemic corticosteroids or estrogen.
• Alcohol or drug abuse

Study Plan

How is the study designed?

Design Details

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

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RT in T2DM; Type 2 diabetes subjects will undergo 3 months of resistance exercise training. Muscle size, strength and response to a low dose amino acids will be measured before and after training. Results of this arm will be compared to those previously obtained in healthy older subjects who participated in NCT02999802 (same training protocol) after 1:1 matching for age and sex.	Behavioral: Resistance exercise training; Supervised resistance exercise training, 3 times a week for 3 months; Other Names: RT
Experimental: BR in healthy subjects, LAA; Healthy subjects will undergo short term bed rest with standard of care physical therapy. Muscle size, strength and response to a low dose amino acids (LAA) will be measured before and after bed rest.	Behavioral: Bed rest; Bed rest for 5 days, followed by standard rehabilitation for 2 days; Other Names: BR
Experimental: BR in healthy subjects, HAA; Healthy subjects will undergo short term bed rest with standard of care physical therapy. Muscle size, strength and response to a high dose amino acids (HAA) will be measured before and after bed rest.	Behavioral: Bed rest; Bed rest for 5 days, followed by standard rehabilitation for 2 days; Other Names: BR
Experimental: BR in T2DM, LAA; Type 2 diabetes (T2DM) subjects will undergo short term bed rest with standard of care physical therapy. Muscle size, strength and response to a low dose amino acids (LAA) will be measured before and after bed rest.	Behavioral: Bed rest; Bed rest for 5 days, followed by standard rehabilitation for 2 days; Other Names: BR
Experimental: BR in T2DM, HAA; Type 2 diabetes (T2DM) subjects will undergo short term bed rest with standard of care physical therapy. Muscle size, strength and response to a high dose amino acids (HAA) will be measured before and after bed rest.	Behavioral: Bed rest; Bed rest for 5 days, followed by standard rehabilitation for 2 days; Other Names: BR
Experimental: BR in healthy subjects, PT; Healthy subjects will undergo short term bed rest with intensive physical therapy (PT). Muscle size, strength and response to a low dose amino acids (LAA) will be measured before and after bed rest.	Behavioral: Bed rest; Bed rest for 5 days, followed by standard rehabilitation for 2 days; Other Names: BR; Behavioral: Intensive physical therapy; Intensive weight bearing PT, daily, during bed rest; Other Names: PT
Experimental: BR in T2DM, PT; Type 2 diabetes (T2DM) subjects will undergo short term bed rest with intensive physical therapy (PT). Muscle size, strength and response to a low dose amino acids (LAA) will be measured before and after bed rest.	Behavioral: Bed rest; Bed rest for 5 days, followed by standard rehabilitation for 2 days; Other Names: BR; Behavioral: Intensive physical therapy; Intensive weight bearing PT, daily, during bed rest; Other Names: PT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leg Lean Mass	Measurement of change in leg lean mass by DEXA	Change from baseline to up to 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Knee Extension Strength	Measurement of change in maximum strength by standard method	Change from baseline to up to 3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amino Acid Transporter Expression	Measurement of change in amino acid transporter expression	Change from baseline to up to 3 months
Muscle Protein Synthesis	Measurement of change in muscle protein synthesis by standard stable isotope methodology	Change from baseline to up to 3 months

Collaborators and Investigators

• Sponsor: The University of Texas Medical Branch, Galveston
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Elena Volpi, MD, PhD, UTMB

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2017
• Primary Completion (Actual): August 21, 2023
• Study Completion (Actual): August 21, 2023

Study Registration Dates

• First Submitted: December 8, 2016
• First Submitted That Met QC Criteria: April 12, 2017
• First Posted (Actual): April 18, 2017

Study Record Updates

• Last Update Posted (Estimated): December 5, 2025
• Last Update Submitted That Met QC Criteria: November 20, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: exercise; nutrition; muscle; amino acids; bed rest
• Additional Relevant MeSH Terms: Neurologic Manifestations; Endocrine System Diseases; Nervous System Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Metabolic Diseases; Glucose Metabolism Disorders; Muscular Atrophy; Atrophy; Pathological Conditions, Signs and Symptoms; Behavior; Nutritional and Metabolic Diseases; Signs and Symptoms; Diabetes Mellitus; Sarcopenia; Motor Activity; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Therapeutics; Physical Therapy Modalities; Patient Care; Exercise Therapy; Rehabilitation; Aftercare; Continuity of Patient Care; Physical Conditioning, Human; Exercise; Resistance Training; Bed Rest
• Other Study ID Numbers: 15-0229/17-0064; R01AG049611 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Small physiological study. Few subjects. Risk of loss of confidentiality

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No