Sex-specific Determinants of Early-phase Recovery From Skeletal Muscle Disuse (MAC)

This project is a 2-phase, randomized clinical trial that includes 7 days of unilateral leg disuse (Phase 1), immediately followed by 14 days of bilateral leg rehabilitation (Phase 2). The investigators will recruit cohorts of healthy middle-aged men and women to address their aims:

• Demonstrate the sex-specific effects of skeletal muscle disuse (Phase 1)
• Identify key molecular determinates of susceptibility of skeletal muscle atrophy (Phase 1)
• Map the early, sex-specific molecular time-course of rehabilitation (Phase 2)
• Determine if disused and healthy muscle respond similarly to exercise (Phase 2)

Healthy, middle-age men and post-menopausal women (50-65 years) will be recruited from the greater Houston/Galveston area. This under-represented research demographic demonstrate few negative metabolic or phenotypic signs of advanced age, but are at increased risk of being hospitalized and experiencing accelerated loss of lean mass and muscle function that parallels a much older population.

The goal of this study is to characterize phenotypic and molecular skeletal muscle changes in middle-aged men and women during critical periods of disuse and rehabilitation and ultimately direct the development of targeted and effective prevention and treatment strategies.

Study Overview

• Status: Recruiting
• Conditions: Rehabilitation; Atrophy of Muscle Due to Disuse
• Intervention / Treatment: Other: Resistance Exercise Rehabilitation; Other: Walking-based rehabilitation

Detailed Description

The negative health consequences of muscular disuse in aging populations are unequivocal. While descriptive, outcome data on disuse and recovery are abundant, key knowledge gaps limit researcher's ability to implement evidence-based, rehabilitation strategies. Limiters include: i) an inability to identify individuals most susceptible to disuse, ii) insufficient information to differentiate between, and respond to, disuse atrophy in men and women, iii) limited insight into the mechanisms driving adaptation to early rehabilitative exercise, and iv) the assumption that disused and healthy skeletal muscle will have a similar, positive response to resistance exercise. The investigators will complete a 2-phase, randomized clinical trial at the University of Texas Medical Branch (UTMB). The protocol includes 7-days of unilateral leg disuse (ULD; Phase 1), immediately followed by 14-days of bilateral leg rehabilitation (Phase 2). Healthy, middle-aged men (n=40) and (post-menopausal) women (n=40), (50-65 y) will be recruited; a neglected research demographic who present with a largely youthful phenotype, but are at risk of accelerated disuse atrophy.

This project will provide a highly powered, detailed phenotypic characterization of the continuum of adults most and least susceptible to muscular disuse. Clinical outcomes will be supported by RNA deep sequencing and pathway analysis to establish a platform that: i) improves scientists' ability to identify higher-risk individuals and ii) provides insight into time-sensitive, sex-specific and effective rehabilitation strategies. Findings and reposed molecular data from this study, may help identify future therapeutic targets and serve as an uncomplicated/comorbidity-free baseline for clinical trials in populations experiencing disuse atrophy.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Blake Rasmussen, PhD; Phone Number: 210-450-7491; Email: rasmussenb@uthscsa.edu
• Study Contact Backup: Name: Sean Kilroe, PhD; Email: kilroe@uthscsa.edu

Study Locations

• United States
  • Texas
    • Galveston, Texas, United States, 77555
      • Completed
      • University of Texas Medical Branch
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • University of Texas Health Science Center at San Antonio
      • Contact: Blake Rasmussen, PhD; Phone Number: 210-450-7491; Email: rasmussenb@uthscsa.edu
      • Contact: Sean Kilroe, PhD; Email: kilroe@uthscsa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. All races and ethnic backgrounds
2. Men and women, age 50-65 years
3. Generally healthy (see exclusion criteria)
4. Able and willing to provide informed consent
5. Ability to speak and read English
6. Post-menopausal women (no menses within the last 12 months)
7. Body mass index: 18.5-35 kg/m2 or BMI>35 if thigh adiposity does not impair muscle biopsy

Exclusion Criteria:

1. Compromised musculoskeletal function that precludes safe participation or use of crutches
2. Pre-menopausal women
3. Hypogonadal men (testosterone <300 ng/dL)
4. Women taking hormone replacement therapy (HRT)
5. Sarcopenia (European Working Group on Sarcopenia in Older People, EWGSOP102)
6. Clinically significant heart disease (e.g. New York Heart Classification greater than grade II; ischemia)
7. Peripheral vascular disease
8. History of claudication
9. Pulmonary disease
10. History of systemic or pulmonary embolus
11. Uncontrolled blood pressure (systolic BP>170, diastolic BP>95 mmHg)
12. Impaired renal function (creatinine >1.5 mg/dl)
13. Anemia (hematocrit <33)
14. Untreated thyroid disease (abnormal TSH)
15. A recent history (<12 months) of GI bleed
16. Diabetes mellitus or other untreated endocrine or metabolic disease
17. Electrolyte abnormalities
18. Any history of stroke, hypo- or hyper-coagulation disorders
19. Employment requiring long (>1 h) uninterrupted period of standing
20. Inability to meet study travel requirements (e.g. manual geared car)
21. Recent history of balance issues or falls.
22. Recent (3 years) treated cancer other than basal cell carcinoma
23. Systemic steroids, anabolic steroids, growth hormone or immunosuppressant use within 12 months
24. Recent (2 months) adherence to a weight-loss or weight-gain diet
25. Weight change of 5% or more in previous 6 months
26. Body mass index >30 or excess body fat that compromises muscle biopsy collection
27. Acute infectious disease or chronic infection
28. Alcohol or drug abuse
29. Any other condition or event considered exclusionary by study physician

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Male Rehabilitation (M-REHAB); Disuse + resistance exercise rehabilitation	Other: Resistance Exercise Rehabilitation; Following disuse, the REHAB groups (M-REHAB, F-REHAB) will complete monitored resistance exercise rehabilitation sessions using an isokinetic dynamometer at a similar relative load at each rehab visit.
Experimental: Male Control (M-CON); Disuse + ambulatory control rehabilitation	Other: Walking-based rehabilitation; Following disuse, the CON groups (M-CON, F-CON) will complete 30 minutes of monitored walking at a moderate intensity at each rehab visit.
Experimental: Female Rehabilitation (F-REHAB); Disuse + resistance exercise rehabilitation	Other: Resistance Exercise Rehabilitation; Following disuse, the REHAB groups (M-REHAB, F-REHAB) will complete monitored resistance exercise rehabilitation sessions using an isokinetic dynamometer at a similar relative load at each rehab visit.
Experimental: Female Control (F-CON); Disuse + ambulatory control rehabilitation	Other: Walking-based rehabilitation; Following disuse, the CON groups (M-CON, F-CON) will complete 30 minutes of monitored walking at a moderate intensity at each rehab visit.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative RNA-sequencing	RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome	Study day 1 (before starting leg disuse)
Quantitative RNA-sequencing	RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome	Study day 7 (after finishing leg disuse)
Quantitative RNA-sequencing	RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome	Study day 7 (after 1 bout of rehabilitation)
Quantitative RNA-sequencing	RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome	Study day 9 (after 2 bouts of rehabilitation)
Quantitative RNA-sequencing	RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome	Study Day 11 (after 3 bouts of rehabilitation)
Quantitative RNA-sequencing	RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome	Study Day 21 (after finishing 7 bouts of rehabilitation)
Muscle function	Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque)	Study day 1 (before starting leg disuse)
Muscle function	Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque)	Study day 7 (after 1 bout of rehabilitation)
Muscle function	Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque)	Study day 9 (after 2 bouts of rehabilitation)
Muscle function	Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque)	Study Day 11 (after 3 bouts of rehabilitation)
Muscle function	Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque)	Study Day 21 (after finishing 7 bouts of rehabilitation)
Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study day 1 (before starting leg disuse)
Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study day 7 (after finishing leg disuse)
Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study day 9 (after 2 bouts of rehabilitation)
Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study Day 11 (after 3 bouts of rehabilitation)
Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study Day 21 (after finishing 7 bouts of rehabilitation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle fiber cross sectional area	Muscle biopsy samples will be evaluated for muscle fiber cross sectional area	Study day 1 (before starting leg disuse)
Muscle fiber cross sectional area	Muscle biopsy samples will be evaluated for muscle fiber cross sectional area	Study day 7 (after finishing leg disuse)
Muscle fiber cross sectional area	Muscle biopsy samples will be evaluated for muscle fiber cross sectional area	Study day 9 (after 2 bouts of rehabilitation)
Muscle fiber cross sectional area	Muscle biopsy samples will be evaluated for muscle fiber cross sectional area	Study Day 11 (after 3 bouts of rehabilitation)
Muscle fiber cross sectional area	Muscle biopsy samples will be evaluated for muscle fiber cross sectional area	Study Day 21 (after finishing 7 bouts of rehabilitation)
Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study day 1 (before starting leg disuse)
Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study day 7 (after finishing leg disuse)
Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study day 9 (after 2 bouts of rehabilitation)
Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study Day 11 (after 3 bouts of rehabilitation)
Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study Day 21 (after finishing 7 bouts of rehabilitation)
Diet recall	A multi-pass 24-hour dietary recall using the Automated Self Assessment 24-h dietary assessment tool to determine habitual food intake	Familiarization session (~1 week before starting leg disuse)
Diet recall	A multi-pass 24-hour dietary recall using the Automated Self Assessment 24-h dietary assessment tool to determine habitual food intake	Study day 11 (after two bouts of rehabilitation)
Physical activity	Accelerometers will placed on the waist and ankle to measure physical activity	Study Days -7 to Day 0 (1 week prior to starting leg disuse)
Physical activity	Accelerometers will placed on the waist and ankle to measure physical activity	Study Days 1-6 (1 week of disuse)
Physical activity	Accelerometers will placed on the waist and ankle to measure physical activity	Study Days 7-21 (2 weeks of rehabilitation)

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Blake Rasmussen, PhD, University of Texas Health Science Center as San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2021
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 9, 2019
• First Submitted That Met QC Criteria: November 1, 2019
• First Posted (Actual): November 5, 2019

Study Record Updates

• Last Update Posted (Actual): December 7, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Atrophy
• Other Study ID Numbers: HSC20230594H; R01AG064386 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected de-identified Individual Participant Data (IPD) that underlie results in a publication. Biological samples will not be available to other/outside investigators, but may be used by the research team for future related assays and experiments.
• IPD Sharing Time Frame: Data will be shared at study completion as summary results on ClinicalTrials.gov and after review and publication in a peer-reviewed journal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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