Alec I McKenzie1, Ziad S Mahmassani2, Jonathan J Petrocelli2, Naomi M M P de Hart3, Dennis K Fix2, Patrick J Ferrara2, Paul C LaStayo2, Robin L Marcus2, Matthew T Rondina4, Scott A Summers3, Jordan M Johnson3, Joel D Trinity5, Katsuhiko Funai6, Micah J Drummond7. 1. Department of Physical Therapy and Athletic Training, University of Utah, 520 Wakara Way, Salt Lake City, UT 84108, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Geriatric Research, Education, and Clinical Center, 500 Foothill Dr., Salt Lake City, UT 84148, USA. 2. Department of Physical Therapy and Athletic Training, University of Utah, 520 Wakara Way, Salt Lake City, UT 84108, USA. 3. Department of Nutrition and Integrative Physiology, University of Utah, 250 S 1850 E, Salt Lake City, UT 84112, USA. 4. Department of Internal Medicine & Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Geriatric Research, Education, and Clinical Center, 500 Foothill Dr., Salt Lake City, UT 84148, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. 5. Department of Nutrition and Integrative Physiology, University of Utah, 250 S 1850 E, Salt Lake City, UT 84112, USA; Department of Internal Medicine & Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Geriatric Research, Education, and Clinical Center, 500 Foothill Dr., Salt Lake City, UT 84148, USA. 6. Department of Physical Therapy and Athletic Training, University of Utah, 520 Wakara Way, Salt Lake City, UT 84108, USA; Department of Nutrition and Integrative Physiology, University of Utah, 250 S 1850 E, Salt Lake City, UT 84112, USA. 7. Department of Physical Therapy and Athletic Training, University of Utah, 520 Wakara Way, Salt Lake City, UT 84108, USA; Department of Nutrition and Integrative Physiology, University of Utah, 250 S 1850 E, Salt Lake City, UT 84112, USA. Electronic address: micah.drummond@hsc.utah.edu.
Abstract
BACKGROUND AND AIMS: Metformin is the most commonly prescribed medication to treat diabetes. Emerging evidence suggests that metformin could have off target effects that might help promote healthy muscle aging, but these effects have not been thoroughly studied in glucose tolerant older individuals. The purpose of this study was to investigate the short-term effects of metformin consumption on skeletal muscle mitochondrial bioenergetics in healthy older adults. METHODS: We obtained muscle biopsy samples from 16 healthy older adults previously naïve to metformin and treated with metformin (METF; 3F, 5M), or placebo (CON; 3F, 5M), for two weeks using a randomized and blinded study design. Samples were analyzed using high-resolution respirometry, immunofluorescence, and immunoblotting to assess muscle mitochondrial bioenergetics, satellite cell (SC) content, and associated protein markers. RESULTS: We found that metformin treatment did not alter maximal mitochondrial respiration rates in muscle compared to CON. In contrast, mitochondrial H2O2 emission and production were elevated in muscle samples from METF versus CON (METF emission: 2.59 ± 0.72 SE Fold, P = 0.04; METF production: 2.29 ± 0.53 SE Fold, P = 0.02). Furthermore, the change in H2O2 emission was positively correlated with the change in type 1 myofiber SC content and this was biased in METF participants (Pooled: R2 = 0.5816, P = 0.0006; METF: R2 = 0.674, P = 0.0125). CONCLUSIONS: These findings suggest that acute exposure to metformin does not impact mitochondrial respiration in aged, glucose-tolerant muscle, but rather, influences mitochondrial-free radical and SC dynamics. CLINICAL TRIAL REGISTRATION: NCT03107884, clinicaltrials.gov.
BACKGROUND AND AIMS: Metformin is the most commonly prescribed medication to treat diabetes. Emerging evidence suggests that metformin could have off target effects that might help promote healthy muscle aging, but these effects have not been thoroughly studied in glucose tolerant older individuals. The purpose of this study was to investigate the short-term effects of metformin consumption on skeletal muscle mitochondrial bioenergetics in healthy older adults. METHODS: We obtained muscle biopsy samples from 16 healthy older adults previously naïve to metformin and treated with metformin (METF; 3F, 5M), or placebo (CON; 3F, 5M), for two weeks using a randomized and blinded study design. Samples were analyzed using high-resolution respirometry, immunofluorescence, and immunoblotting to assess muscle mitochondrial bioenergetics, satellite cell (SC) content, and associated protein markers. RESULTS: We found that metformin treatment did not alter maximal mitochondrial respiration rates in muscle compared to CON. In contrast, mitochondrial H2O2 emission and production were elevated in muscle samples from METF versus CON (METF emission: 2.59 ± 0.72 SE Fold, P = 0.04; METF production: 2.29 ± 0.53 SE Fold, P = 0.02). Furthermore, the change in H2O2 emission was positively correlated with the change in type 1 myofiber SC content and this was biased in METF participants (Pooled: R2 = 0.5816, P = 0.0006; METF: R2 = 0.674, P = 0.0125). CONCLUSIONS: These findings suggest that acute exposure to metformin does not impact mitochondrial respiration in aged, glucose-tolerant muscle, but rather, influences mitochondrial-free radical and SC dynamics. CLINICAL TRIAL REGISTRATION: NCT03107884, clinicaltrials.gov.
Authors: Paul T Reidy; Catherine C Lindsay; Alec I McKenzie; Christopher S Fry; Mark A Supiano; Robin L Marcus; Paul C LaStayo; Micah J Drummond Journal: Exp Gerontol Date: 2017-07-10 Impact factor: 4.032
Authors: Barry Braun; Pamela Eze; Brooke R Stephens; Todd A Hagobian; Carrie G Sharoff; Stuart R Chipkin; Benjamin Goldstein Journal: Appl Physiol Nutr Metab Date: 2008-02 Impact factor: 2.665
Authors: Doug E Long; Bailey D Peck; Jenny L Martz; S Craig Tuggle; Heather M Bush; Gerald McGwin; Philip A Kern; Marcas M Bamman; Charlotte A Peterson Journal: Trials Date: 2017-04-26 Impact factor: 2.279
Authors: Adam R Konopka; Jaime L Laurin; Hayden M Schoenberg; Justin J Reid; William M Castor; Christopher A Wolff; Robert V Musci; Oscar D Safairad; Melissa A Linden; Laurie M Biela; Susan M Bailey; Karyn L Hamilton; Benjamin F Miller Journal: Aging Cell Date: 2018-12-11 Impact factor: 9.304
Authors: Hui Yu; Jolena N Waddell; Shihuan Kuang; Ross L Tellam; Noelle E Cockett; Christopher A Bidwell Journal: BMC Genomics Date: 2018-04-24 Impact factor: 3.969