Metformin and Muscle Recovery

Last updated: November 7, 2024
Sponsor: University of Utah
Overall Status: Active - Recruiting

Phase

1

Condition

Muscular Dystrophy

Myasthenia Gravis (Chronic Weakness)

Treatment

Placebo

Metformin

Clinical Study ID

NCT06185179
086328
  • Ages > 60
  • All Genders
  • Accepts Healthy Volunteers

Study Summary

A hallmark of aging is an impaired ability to adequately recover following a stressor, such as muscle disuse, resulting in muscle fibrosis and weakness thereby increasing the risk for falls and loss of independence. Mechanistic-based therapeutic strategies to enhance muscle recovery in older adults do not exist. Metformin has been implicated to have positive effects on muscle size and function through non-glycemic mechanisms. Metformin has been shown to enhance macrophage function and lessen cellular senescence burden by targeting SASP in a variety of muscle interstitial cells. However, the role of metformin to improve muscle recovery in older adults following disuse atrophy through immunomodulating and senomorphic mechanisms have not been examined. Therefore, the purpose of this study is to conduct a randomized, double blind, placebo-controlled clinical trial in older adult participants to determine if short-term metformin delivery (vs placebo) during the recovery phase following disuse atrophy can improve muscle regrowth.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Age between 60y and older

  2. BMI: <30 kg/m2

  3. Good general medical health, ambulatory and in independent living setting

  4. Adequate upper body strength to use assistive walking device (crutches, walker, etc)as assessed by PI/staff during screening

  5. Clinical Frailty Scale score < 3

  6. Mini-Cog score > 3

Exclusion

Exclusion Criteria:

  1. History of cardiovascular disease (e.g., CHF, CAD, MI, CVA)

  2. History of endocrine or metabolic disease such as hypo/hyperthyroidism and diabetes (Treated hypo/hyperthyroid for at least 6 months will be permitted)

  3. History of kidney disease or failure (CKD > stage 4; serum creatinine >1.5mg/dL)

  4. History of vascular disease

  5. Risk of DVT including family history of thrombophilia, DVT, pulmonary emboli,myeloproliferative diseases including polycythemia (Hb>18 g/dL) or thrombocytosis (platelets>400x103/mL), and connective tissue diseases (positive lupusanticoagulant), hyperhomocystinemia, deficiencies of factor V Leiden, proteins S andC, and antithrombine III

  6. Use of anticoagulant therapy (e.g., Coumadin, heparin)

  7. Uncontrolled hypertension - Elevated systolic pressure >150 or a diastolic bloodpressure > 100

  8. Implanted electronic devices (e.g., pacemakers, electronic infusion pumps,stimulators)

  9. Cancer or history of successfully treated cancer (less than 1 year) other than basalcell carcinoma

  10. Chronic systemic corticosteroid use (≥ 2 weeks) within 4 weeks of enrollment and forstudy duration (intra-articular/topical/inhaled therapeutic or physiologic doses ofcorticosteroids will be permitted)

  11. Androgens or growth hormone within 6 months of enrollment and for study duration (topical physiologic androgen replacement will be permitted)

  12. Inability to abstain from smoking or vaping for duration of study

  13. Currently taking estrogen products (topical estrogen products will be permitted)

  14. Currently on weight loss diet or medication

  15. History of stroke with motor disability

  16. A recent history (<12 months) of GI bleed

  17. History of liver disease or AST/ALT 2 times above the normal limit

  18. History of respiratory disease (acute upper respiratory infection, history ofchronic lung disease)

  19. Any staff members who report directly to the principal investigators

Study Design

Total Participants: 50
Treatment Group(s): 2
Primary Treatment: Placebo
Phase: 1
Study Start date:
September 01, 2024
Estimated Completion Date:
May 31, 2030

Study Description

Aging is associated with impaired muscle recovery following disuse atrophy. If not addressed, restricted muscle regrowth and function may lead to a cascade of health crisis events for the aged individual (falls, disability, metabolic diseases). Clinically adopted treatments that promote muscle recovery, particularly in elderly patients, do not exist. The long-term goal of this project is to develop mechanistic-based therapeutic approaches to accelerate muscle recovery following disuse atrophy in older adults.

Macrophages are well understood to play a requisite role in myofiber remodeling including removal of debris and senescent cells, promotion of stem/satellite cell proliferation and differentiation, and regulation fibro-adipogenic progenitor cell (FAP) dynamics and fate. It is known that aged muscle during recovery have an impaired macrophage inflammatory and functional response complimented with poor muscle recovery. The investigators posit that age-related local immune dysfunction disrupts extracellular matrix (ECM) remodeling following muscle disuse by reducing the removal of senescence cells resulting in their accumulation. Therefore, treatments are needed to improve macrophage function and mitigate cellular senescence to facilitate muscle cellular remodeling events (e.g., macrophage, satellite cells, FAPs) during recovery following disuse in aging.

Metformin has gained traction to be repurposed as a treatment for a broad range of age-related diseases but its role in regulating muscle regrowth following disuse atrophy in humans is not known. Metformin has shown to modulate inflammatory profiles, mitigate cellular senescence and SASP (e.g., macrophages, FAPs, and myoblasts) while also improving muscle regeneration and satellite cell function in injured mice. Therefore, metformin treatment could have therapeutic value to temper unwanted collagen deposition and promote muscle regrowth and function when strategically delivered during the muscle regrowth phase in aging by targeting immune cell function and cellular senescence and SASP.

The overarching hypothesis is that metformin would mitigate cellular senescence and SASP specifically in macrophages, FAPs and satellite cells and would correspond to enhanced muscle function following disuse atrophy. The investigators will conduct a randomized, placebo-controlled clinical trial in healthy older participants to test if metformin provided during a 14d recovery phase following unilateral limb immobilization would improve muscle macrophage, FAP and satellite cell function, reduce cellular senescence and muscle fibrosis.

Connect with a study center

  • University of Utah

    Salt Lake City, Utah 84112
    United States

    Active - Recruiting

Not the study for you?

Let us help you find the best match. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.