Role of Metformin on Muscle Health of Older Adults

Muscle atrophy and insulin resistance are common after bed rest in healthy older adults. Metformin treatment has been shown to improve insulin sensitivity and attenuate muscle loss in insulin resistance adults though the mechanisms are not fully known. Metformin used as a preventive strategy to maintain muscle and metabolic health in bed ridden older adults has not been investigated.

Hospitalizations for disease, injury, and/or surgery in older adults are likely to impair physical mobility and, therefore, the older adults capacity to be physically active both during hospitalization and beyond. The resulting sedentary lifestyle is likely to be accepted as the "new normal", ultimately increasing the risk of skeletal muscle and metabolic dysfunction (e.g. insulin resistance and sarcopenia). Muscle atrophy and insulin resistance are an unfortunate consequence with disuse in older adults. We have observed with our bed rest studies in healthy older adults that in addition to muscle and metabolic changes, we notice increased skeletal muscle inflammation, impaired glucose uptake signaling and an upregulation of enzymes related to de novo ceramide biosynthesis. The accumulation of ceramide, a toxic lipid intermediate, can disrupt glucose homeostasis and impair muscle growth. Metformin treatment has been shown to improve insulin sensitivity and attenuate muscle loss in insulin resistant adults through a mechanism that may involve ceramide synthesis. Metformin used as a preventive strategy to maintain muscle and metabolic health during a period of physical inactivity in older adults has not been investigated. A separate group of participants for the 2-week Metformin Run-in Period, independent of the bed rest and recovery study will also be recruited. All study procedures will be the same as the 2-week Run-In period within the full protocol. We hypothesize that metformin treatment in healthy older adults during bed rest would attenuate inflammation, insulin resistance, and thigh muscle loss and changes in lipid accumulating in muscle. We also hypothesize that elevated skeletal muscle ceramide levels, is central to the development of insulin resistance with bed rest in older adults. Therefore, we have proposed to conduct a clinical study in older adults to: Test if daily metformin treatment (vs placebo) during 5d of bed rest in older adults would attenuate intramuscular ceramide accumulation (lipid accumulation), insulin resistance (euglycemic-hyperinsulinemic clamp), and loss in thigh muscle lean mass. We would also like to determine if 5-days of bed rest in older adults within the placebo group increases skeletal muscle ceramide concentrations and whether these are in turn associated with insulin resistance. Test if daily metformin treatment (vs placebo) during 5d of bed rest in older adults would improve skeletal muscle glucose uptake cell signaling, reduce skeletal muscle inflammation and ceramide biosynthesis signaling. Determine if muscle ceramides and insulin resistance return to baseline levels following 7 days of recovery after bed rest in the placebo group. Determine if metformin given over a 2 week period (independent of bed rest) will improve muscle size, strength and insulin sensitivity. Determine if metformin improves the recovery of muscle size and strength and insulin sensitivity 7 days after bed rest. These findings will be foundational for future development of treatments to prevent insulin resistance and muscle atrophy in inactive older adults.

Insulin Resistance, Muscle Atrophy, Metformin, Muscle Loss, Inactivity-induced muscle loss, older adults

drug and placebo will be encapsulated therefore concealing the participant, investigator and outcome assessor to group assignment.

Metformin will be given to participants incrementally during a 2 week run in period such that they will receive the clinical dose (2 grams per day). During bed rest, participants will be given 1 gram of metformin two times a day (morning and evening). This dosage and frequency will occur during four consecutive days of bed rest.

Placebo will be given to participants incrementally during a 2 week run in period such that they will receive the same amount of pills as the experimental group. During bed rest, participants will be given the same amount of pills and given at the same time of day (morning and evening) as the experimental group. This strategy will occur during four consecutive days of bed rest.

Metformin will be given to participants incrementally during a 2 week run in period such that they will receive the clinical dose (2 grams per day). These participants will not participate in the bed rest portion of the protocol.

Placebo will be given to participants incrementally during a 2 week run in period such that they will receive the same amount of pills as the experimental group. These participants will not participate in the bed rest portion of the protocol.

Placebo-comparator. The same quantity of non-active tablets will be given at the same time of day as the Metformin treatment group

A clinical oral dose of Metformin will be given to participant daily during a two week run-in period only.

Placebo-comparator. The same quantity of non-active tablets will be given at the same time of day as the Metformin 2 week run-in treatment group.

Change in muscle size from baseline to 5-days of bed rest will be compared between groups after 5 days of bed rest

Change in insulin sensitivity from baseline to 5-days of bed rest (determined from glucose infusion rate)

Change in insulin sensitivity from baseline to 5-days of bed rest will be compared between groups after 5 days of bed rest

Inclusion Criteria: Age 60y and older Ability to sign informed consent Free-living, prior to admission Exclusion Criteria: Personal history of cardiovascular disease Uncontrolled endocrine or metabolic disease (e.g., hypo/hyperthyroidism, HbA1c ≥6.5%) Evidence of kidney disease or failure (defined as serum creatinine > 1.5mg/dL) Vascular disease or risk factors of peripheral atherosclerosis. (e.g., uncontrolled hypertension, obesity, diabetes) Risk of Deep vein thrombosis including family history of thrombophilia, Deep vein thrombosis, pulmonary emboli, myeloproliferative diseases including polycythemia (Hb>18 g/dL) or thrombocytosis (platelets>400x103/mL) Use of anticoagulant therapy (e.g., Coumadin, heparin) Uncontrolled hypertension (e.g. systolic pressure >160 or a diastolic blood pressure > 100) Cancer or history of successfully treated cancer (less than 1 year) other than basal cell carcinoma Currently on a weight-loss diet or body mass index > 30 kg/m2 Inability to abstain from smoking for duration of study HIV or hepatitis B or C* Subjects excluded due to positive screening results, including HIV, hepatitis B or hepatitis C, will be immediately scheduled for counseling and follow-up testing as needed, and will be advised to consult their primary physician. 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 are permitted). Androgens or growth hormone within 6 months of enrollment and for study duration (topical physiologic androgen replacement is permitted) Subjects with hemoglobin or hematocrit lower than accepted lab values History of stroke with motor disability A recent history (<12 months) of GI bleed Depression [>5 on the 15 items Geriatric Depression Scale (GDS)]* *This criteria will only apply to subjects in the bed rest arm. Liver disease (the ratio of serum aspartate aminotransferase to serum alanine aminotransferase 2 times above the normal limit, hyperbilirubinemia) History of respiratory disease Currently taking estrogen products (topical vaginal products are not exclusionary (e.g. cream)) Recent travel history as defined by 4 hours of travel by airplane in the last week Any other condition or event considered exclusionary by the PI and faculty physician

McKenzie AI, Mahmassani ZS, Petrocelli JJ, de Hart NMMP, Fix DK, Ferrara PJ, LaStayo PC, Marcus RL, Rondina MT, Summers SA, Johnson JM, Trinity JD, Funai K, Drummond MJ. Short-term exposure to a clinical dose of metformin increases skeletal muscle mitochondrial H2O2 emission and production in healthy, older adults: A randomized controlled trial. Exp Gerontol. 2022 Jun 15;163:111804. doi: 10.1016/j.exger.2022.111804. Epub 2022 Apr 9.