Metformin and Muscle Recovery

Study Overview
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Brief Summary
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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 adults to determine if short-term metformin delivery (vs placebo) during the recovery phase following disuse atrophy can improve muscle regrowth.

Detailed Description
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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. Our long-term goal 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. We and others note that aged muscle during recovery have an impaired macrophage inflammatory and functional response complimented with poor muscle recovery. We 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. Our 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. We will conduct a randomized, placebo-controlled clinical trial in healthy older adults 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.

Official Title
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Use of Metformin to Improve Muscle Regrowth in Older Adults

Conditions
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Muscle Atrophy or Weakness

Intervention / Treatment
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* Drug: Metformin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 60y and older BMI: <30 kg/m2 Good general medical health, ambulatory and in independent living setting Adequate upper body strength to use assistive walking device (crutches, walker, etc) as assessed by PI/staff during screening Clinical Frailty Scale score < 3 Mini-Cog score > 3 Exclusion Criteria: History of cardiovascular disease (e.g., CHF, CAD, MI, CVA) History of endocrine or metabolic disease such as hypo/hyperthyroidism and diabetes (Treated hypo/hyperthyroid for at least 6 months will be permitted) History of kidney disease or failure (CKD > stage 4; serum creatinine >1.5mg/dL) History of vascular disease 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 lupus anticoagulant), hyperhomocystinemia, deficiencies of factor V Leiden, proteins S and C, and antithrombine III Use of anticoagulant therapy (e.g., Coumadin, heparin) Uncontrolled hypertension - Elevated systolic pressure >150 or a diastolic blood pressure > 100 Implanted electronic devices (e.g., pacemakers, electronic infusion pumps, stimulators) Cancer or history of successfully treated cancer (less than 1 year) other than basal cell carcinoma Chronic systemic corticosteroid use (≥ 2 weeks) within 4 weeks of enrollment and for study duration (intra-articular/topical/inhaled therapeutic or physiologic doses of corticosteroids will be permitted) Androgens or growth hormone within 6 months of enrollment and for study duration (topical physiologic androgen replacement will be permitted) Inability to abstain from smoking or vaping for duration of study Currently taking estrogen products (topical estrogen products will be permitted) Currently on weight loss diet or medication History of stroke with motor disability A recent history (<12 months) of GI bleed History of liver disease or AST/ALT 2 times above the normal limit History of respiratory disease (acute upper respiratory infection, history of chronic lung disease) Any staff members who report directly to the principal investigators

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2-weeks single leg immobilization followed by 2-weeks of recovery
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin pills will be given orally and daily during the 2-week recovery period following single leg immobilization Metformin will be titrated up to a dose 2g/day. 1g dose (two 500 mg pills) will be taken in the morning and a 1g dose will be taken in the evening. This will take place over each day for 14 days during the recovery period. | Drug: Metformin<br>* Metformin will be distributed in 500mg pills.<br>* Other names: Riomet;|
| Placebo Comparator: Placebo<br>Placebo pills will be given orally and daily during the 2-week recovery period following single leg immobilization. Two pills will be taken in the morning and two pills will be taken in the evening. This will take place over each day for 14 days during the recovery period. | Other: Placebo<br>* Placebo will be distributed in pill form<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % recovery of thigh muscle volume (TMV) | recovery of thigh muscle volume will be defined as the percentage of TMV at recovery when comparing to the TMV immobilization time point ((TMV recovery - TMV immobilization)/TMV immobilization)*100. Thigh muscle volume will be determined by MRI. | Thigh muscle volume will be determined at 14 days of single leg immobilization and at 14 days of recovery. |