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

Rehabilitation Clinical Trial

— MAC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04151901
• Other study ID #: HSC20230594H
• Secondary ID: R01AG064386
• Status: Recruiting
• Phase: N/A
• Start date: August 27, 2021
• Est. completion date: December 2026

Study information

• Verified date: November 2023
• Source: The University of Texas Health Science Center at San Antonio
• Contact: Blake Rasmussen, PhD
• Phone: 210-450-7491
• Email: rasmussenb[@]uthscsa.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: December 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 50 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Atrophy
• Atrophy of Muscle Due to Disuse
• Rehabilitation

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of Texas Medical Branch	Galveston	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study day 1 (before starting leg disuse)
Primary	Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study day 7 (after finishing leg disuse)
Primary	Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study day 9 (after 2 bouts of rehabilitation)
Primary	Body (leg) composition	Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry	Study Day 11 (after 3 bouts of rehabilitation)
Primary	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	Muscle fiber cross sectional area	Muscle biopsy samples will be evaluated for muscle fiber cross sectional area	Study day 1 (before starting leg disuse)
Secondary	Muscle fiber cross sectional area	Muscle biopsy samples will be evaluated for muscle fiber cross sectional area	Study day 7 (after finishing leg disuse)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study day 1 (before starting leg disuse)
Secondary	Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study day 7 (after finishing leg disuse)
Secondary	Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study day 9 (after 2 bouts of rehabilitation)
Secondary	Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study Day 11 (after 3 bouts of rehabilitation)
Secondary	Muscle fiber type	Muscle biopsy samples will be evaluated for muscle fiber type distribution	Study Day 21 (after finishing 7 bouts of rehabilitation)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Physical activity	Accelerometers will placed on the waist and ankle to measure physical activity	Study Days 1-6 (1 week of disuse)
Secondary	Physical activity	Accelerometers will placed on the waist and ankle to measure physical activity	Study Days 7-21 (2 weeks of rehabilitation)