Title

Differences in Mitochondrial Coupling Reveal a Novel Signature of Mitohormesis in Muscle of Healthy Individuals

Authors

Lauren M. Sparks, Translational Research Institute for Metabolism and Diabetes (L.M.S., F.Y., C.S., H.H.C., S.R.S.), Florida Hospital, Orlando, Florida 32804; Clinical and Molecular Origins of Disease (L.M.S., M.E.G., S.R.S.), Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827; Pennington Biomedical Research Center (L.M.R., E.R.), Louisiana State University System, Baton Rouge, Louisiana 70808; Departments of Radiology, Physiology and Biophysics, and Bioengineering (K.E.C.), University of Washington Medical Center, Seattle, Washington 98195; Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario ON K1N 6N5, Canada; Bioinformatics Core (A.H., A.E.), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037; and Hospital for Sick Children (S.R.C.), Toronto, Ontario, ON M5G 1X8 Canada.
Leanne M. Redman, Translational Research Institute for Metabolism and Diabetes (L.M.S., F.Y., C.S., H.H.C., S.R.S.), Florida Hospital, Orlando, Florida 32804; Clinical and Molecular Origins of Disease (L.M.S., M.E.G., S.R.S.), Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827; Pennington Biomedical Research Center (L.M.R., E.R.), Louisiana State University System, Baton Rouge, Louisiana 70808; Departments of Radiology, Physiology and Biophysics, and Bioengineering (K.E.C.), University of Washington Medical Center, Seattle, Washington 98195; Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario ON K1N 6N5, Canada; Bioinformatics Core (A.H., A.E.), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037; and Hospital for Sick Children (S.R.C.), Toronto, Ontario, ON M5G 1X8 Canada.
Kevin E. Conley, Translational Research Institute for Metabolism and Diabetes (L.M.S., F.Y., C.S., H.H.C., S.R.S.), Florida Hospital, Orlando, Florida 32804; Clinical and Molecular Origins of Disease (L.M.S., M.E.G., S.R.S.), Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827; Pennington Biomedical Research Center (L.M.R., E.R.), Louisiana State University System, Baton Rouge, Louisiana 70808; Departments of Radiology, Physiology and Biophysics, and Bioengineering (K.E.C.), University of Washington Medical Center, Seattle, Washington 98195; Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario ON K1N 6N5, Canada; Bioinformatics Core (A.H., A.E.), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037; and Hospital for Sick Children (S.R.C.), Toronto, Ontario, ON M5G 1X8 Canada.
Mary-Ellen Harper, Translational Research Institute for Metabolism and Diabetes (L.M.S., F.Y., C.S., H.H.C., S.R.S.), Florida Hospital, Orlando, Florida 32804; Clinical and Molecular Origins of Disease (L.M.S., M.E.G., S.R.S.), Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827; Pennington Biomedical Research Center (L.M.R., E.R.), Louisiana State University System, Baton Rouge, Louisiana 70808; Departments of Radiology, Physiology and Biophysics, and Bioengineering (K.E.C.), University of Washington Medical Center, Seattle, Washington 98195; Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario ON K1N 6N5, Canada; Bioinformatics Core (A.H., A.E.), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037; and Hospital for Sick Children (S.R.C.), Toronto, Ontario, ON M5G 1X8 Canada.
Andrew Hodges, Translational Research Institute for Metabolism and Diabetes (L.M.S., F.Y., C.S., H.H.C., S.R.S.), Florida Hospital, Orlando, Florida 32804; Clinical and Molecular Origins of Disease (L.M.S., M.E.G., S.R.S.), Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827; Pennington Biomedical Research Center (L.M.R., E.R.), Louisiana State University System, Baton Rouge, Louisiana 70808; Departments of Radiology, Physiology and Biophysics, and Bioengineering (K.E.C.), University of Washington Medical Center, Seattle, Washington 98195; Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario ON K1N 6N5, Canada; Bioinformatics Core (A.H., A.E.), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037; and Hospital for Sick Children (S.R.C.), Toronto, Ontario, ON M5G 1X8 Canada.
Alexey Eroshkin, Translational Research Institute for Metabolism and Diabetes (L.M.S., F.Y., C.S., H.H.C., S.R.S.), Florida Hospital, Orlando, Florida 32804; Clinical and Molecular Origins of Disease (L.M.S., M.E.G., S.R.S.), Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827; Pennington Biomedical Research Center (L.M.R., E.R.), Louisiana State University System, Baton Rouge, Louisiana 70808; Departments of Radiology, Physiology and Biophysics, and Bioengineering (K.E.C.), University of Washington Medical Center, Seattle, Washington 98195; Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario ON K1N 6N5, Canada; Bioinformatics Core (A.H., A.E.), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037; and Hospital for Sick Children (S.R.C.), Toronto, Ontario, ON M5G 1X8 Canada.
Sheila R. Costford, Translational Research Institute for Metabolism and Diabetes (L.M.S., F.Y., C.S., H.H.C., S.R.S.), Florida Hospital, Orlando, Florida 32804; Clinical and Molecular Origins of Disease (L.M.S., M.E.G., S.R.S.), Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827; Pennington Biomedical Research Center (L.M.R., E.R.), Louisiana State University System, Baton Rouge, Louisiana 70808; Departments of Radiology, Physiology and Biophysics, and Bioengineering (K.E.C.), University of Washington Medical Center, Seattle, Washington 98195; Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario ON K1N 6N5, Canada; Bioinformatics Core (A.H., A.E.), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037; and Hospital for Sick Children (S.R.C.), Toronto, Ontario, ON M5G 1X8 Canada.
Meghan E. Gabriel, Translational Research Institute for Metabolism and Diabetes (L.M.S., F.Y., C.S., H.H.C., S.R.S.), Florida Hospital, Orlando, Florida 32804; Clinical and Molecular Origins of Disease (L.M.S., M.E.G., S.R.S.), Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827; Pennington Biomedical Research Center (L.M.R., E.R.), Louisiana State University System, Baton Rouge, Louisiana 70808; Departments of Radiology, Physiology and Biophysics, and Bioengineering (K.E.C.), University of Washington Medical Center, Seattle, Washington 98195; Department of Biochemistry, Microbiology, and Immunology (M.-E.H.), University of Ottawa, Ottawa, Ontario ON K1N 6N5, Canada; Bioinformatics Core (A.H., A.E.), Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037; and Hospital for Sick Children (S.R.C.), Toronto, Ontario, ON M5G 1X8 Canada.

Document Type

Article

Publication Date

12-1-2016

Abstract

CONTEXT: Reduced mitochondrial coupling (ATP/O [P/O]) is associated with sedentariness and insulin resistance. Interpreting the physiological relevance of P/O measured in vitro is challenging. OBJECTIVE: To evaluate muscle mitochondrial function and associated transcriptional profiles in nonobese healthy individuals distinguished by their in vivo P/O. DESIGN: Individuals from an ancillary study of Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy phase 2 were assessed at baseline. SETTING: The study was performed at Pennington Biomedical Research Center. PARTICIPANTS: Forty-seven (18 males, 26-50 y of age) sedentary, healthy nonobese individuals were divided into 2 groups based on their in vivo P/O. INTERVENTION: None. Main Outcome(s): Body composition by dual-energy x-ray absorptiometry, in vivo mitochondrial function (P/O and maximal ATP synthetic capacity) by P-magnetic resonance spectroscopy and optical spectroscopy were measured. A muscle biopsy was performed to measure fiber type, transcriptional profiling (microarray), and protein expressions. RESULTS: No differences in body composition, peak aerobic capacity, type I fiber content, or mitochondrial DNA copy number were observed between the 2 groups. Compared with the uncoupled group (lower P/O), the coupled group (higher P/O) had higher rates of maximal ATP synthetic capacity (maximal ATP synthetic capacity, P < .01). Transcriptomics analyses revealed higher expressions of genes involved in mitochondrial remodeling and the oxidative stress response in the coupled group. A trend for higher mitonuclear protein imbalance (P = .06) and an elevated mitochondrial unfolded protein response (heat shock protein 60 protein; P = .004) were also identified in the coupled group. CONCLUSIONS: Higher muscle mitochondrial coupling is accompanied by an overall elevation in mitochondrial function, a novel transcriptional signature of oxidative stress and mitochondrial remodeling and indications of an mitochondrial unfolded protein response.

Publication Source (Journal or Book title)

The Journal of clinical endocrinology and metabolism

First Page

4994

Last Page

5003

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