title: Differences in Mitochondrial Coupling Reveal a Novel Signature of Mitohormesis in Muscle of Healthy Individuals.
abstract: Reduced mitochondrial coupling (ATP/O2[P/O]) is associated with sedentariness and insulin resistance. Interpreting the physiological relevance of P/O measured in vitro is challenging.
  
  
  
  To evaluate muscle mitochondrial function and associated transcriptional profiles in nonobese healthy individuals distinguished by their in vivo P/O.
  
  
  
  Individuals from an ancillary study of Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy phase 2 were assessed at baseline.
  
  
  
  The study was performed at Pennington Biomedical Research Center.
  
  
  
  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.
  
  
  
  None. Main Outcome(s): Body composition by dual-energy x-ray absorptiometry, in vivo mitochondrial function (P/O and maximal ATP synthetic capacity) by31P-magnetic resonance spectroscopy and optical spectroscopy were measured. A muscle biopsy was performed to measure fiber type, transcriptional profiling (microarray), and protein expressions.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Sparks
authors.affiliation: 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.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Redman
authors.affiliation: 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.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Conley
authors.affiliation: 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.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hodges
authors.affiliation: 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.
authors.forename: Alexey
authors.initials: A
authors.lastname: Eroshkin
authors.affiliation: 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.
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Costford
authors.affiliation: 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.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Gabriel
authors.affiliation: 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.
authors.forename: Fanchao
authors.initials: F
authors.lastname: Yi
authors.affiliation: 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.
authors.forename: Cherie
authors.initials: C
authors.lastname: Shook
authors.affiliation: 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.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Cornnell
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Ravussin
authors.affiliation: 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.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
mesh_terms: D015502:Absorptiometry, Photon; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D005260:Female; D020869:Gene Expression Profiling; D059165:Hormesis; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D058451:Oxidative Coupling; D018384:Oxidative Stress; D010101:Oxygen Consumption; D057185:Sedentary Behavior
chemical_list: D000255:Adenosine Triphosphate