OBJECTIVE: The skeletal muscle of obese humans is characterized by an inability to appropriately respond to alterations in substrate availability. The purpose of this study was to determine if this metabolic inflexibility with obesity is retained in mitochondria of human skeletal muscle cells raised in culture (HSkMC) and to identify potential mechanisms involved. DESIGN: Mitochondrial respiration was measured in permeabilized myotubes cultured from lean and obese individuals before and after a 24-h lipid incubation. RESULTS: Mitochondrial respiration (state 3) in the presence of lipid substrate (palmitoyl carnitine) increased by almost twofold after lipid incubation in HSkMC from lean, but not obese subjects, indicative of metabolic inflexibility with obesity. The 24-h lipid incubation increased mitochondrial DNA (mtDNA) copy number in HSkMC from lean subjects by +16% (P<0.05); conversely, mtDNA copy number decreased in myotubes cultured from obese individuals (-13%, P=0.06). When respiration data were normalized to mtDNA copy number and other indices of mitochondrial content (COX-IV protein content and CS activity), the significant treatment effects of lipid incubation persisted in the lean subjects, suggesting concomitant alterations in mitochondrial function; no similar adjustment was evident in HSkMC from obese individuals. CONCLUSION: These data indicate that the skeletal muscle of obese individuals inherently lacks metabolic flexibility in response to lipid exposure, which consists of an inability to increase mitochondrial respiration in the presence of lipid substrate and perhaps by an inability to induce mitochondrial proliferation.
OBJECTIVE: The skeletal muscle of obesehumans is characterized by an inability to appropriately respond to alterations in substrate availability. The purpose of this study was to determine if this metabolic inflexibility with obesity is retained in mitochondria of human skeletal muscle cells raised in culture (HSkMC) and to identify potential mechanisms involved. DESIGN: Mitochondrial respiration was measured in permeabilized myotubes cultured from lean and obese individuals before and after a 24-h lipid incubation. RESULTS: Mitochondrial respiration (state 3) in the presence of lipid substrate (palmitoyl carnitine) increased by almost twofold after lipid incubation in HSkMC from lean, but not obese subjects, indicative of metabolic inflexibility with obesity. The 24-h lipid incubation increased mitochondrial DNA (mtDNA) copy number in HSkMC from lean subjects by +16% (P<0.05); conversely, mtDNA copy number decreased in myotubes cultured from obese individuals (-13%, P=0.06). When respiration data were normalized to mtDNA copy number and other indices of mitochondrial content (COX-IV protein content and CS activity), the significant treatment effects of lipid incubation persisted in the lean subjects, suggesting concomitant alterations in mitochondrial function; no similar adjustment was evident in HSkMC from obese individuals. CONCLUSION: These data indicate that the skeletal muscle of obese individuals inherently lacks metabolic flexibility in response to lipid exposure, which consists of an inability to increase mitochondrial respiration in the presence of lipid substrate and perhaps by an inability to induce mitochondrial proliferation.
Authors: Leslie A Consitt; Jill A Bell; Timothy R Koves; Deborah M Muoio; Matthew W Hulver; Kimberly R Haynie; G Lynis Dohm; Joseph A Houmard Journal: Diabetes Date: 2010-03-03 Impact factor: 9.461
Authors: Jill A Bell; Melissa A Reed; Leslie A Consitt; Ola J Martin; Kimberly R Haynie; Matthew W Hulver; Deborah M Muoio; G Lynis Dohm Journal: J Clin Endocrinol Metab Date: 2010-04-28 Impact factor: 5.958
Authors: K E Boyle; J P Canham; L A Consitt; D Zheng; T R Koves; T P Gavin; D Holbert; P D Neufer; O Ilkayeva; D M Muoio; J A Houmard Journal: J Clin Endocrinol Metab Date: 2010-12-29 Impact factor: 5.958
Authors: Ethan J Anderson; Mary E Lustig; Kristen E Boyle; Tracey L Woodlief; Daniel A Kane; Chien-Te Lin; Jesse W Price; Li Kang; Peter S Rabinovitch; Hazel H Szeto; Joseph A Houmard; Ronald N Cortright; David H Wasserman; P Darrell Neufer Journal: J Clin Invest Date: 2009-02-02 Impact factor: 14.808
Authors: Andrew Philp; Joaquin Perez-Schindler; Charlotte Green; D Lee Hamilton; Keith Baar Journal: Am J Physiol Cell Physiol Date: 2010-04-21 Impact factor: 4.249
Authors: Natalie Lefort; Brian Glancy; Benjamin Bowen; Wayne T Willis; Zachary Bailowitz; Elena A De Filippis; Colleen Brophy; Christian Meyer; Kurt Højlund; Zhengping Yi; Lawrence J Mandarino Journal: Diabetes Date: 2010-08-03 Impact factor: 9.461
Authors: Sushabhan Sadhukhan; Xiaojing Liu; Dongryeol Ryu; Ornella D Nelson; John A Stupinski; Zhi Li; Wei Chen; Sheng Zhang; Robert S Weiss; Jason W Locasale; Johan Auwerx; Hening Lin Journal: Proc Natl Acad Sci U S A Date: 2016-04-05 Impact factor: 11.205
Authors: Carrie E McCurdy; Simon Schenk; Byron Hetrick; Julie Houck; Brian G Drew; Spencer Kaye; Melanie Lashbrook; Bryan C Bergman; Diana L Takahashi; Tyler A Dean; Travis Nemkov; Ilya Gertsman; Kirk C Hansen; Andrew Philp; Andrea L Hevener; Adam J Chicco; Kjersti M Aagaard; Kevin L Grove; Jacob E Friedman Journal: JCI Insight Date: 2016-10-06
Authors: Tai-Yu Huang; Donghai Zheng; Joseph A Houmard; Jeffrey J Brault; Robert C Hickner; Ronald N Cortright Journal: Am J Physiol Endocrinol Metab Date: 2017-01-10 Impact factor: 4.310
Authors: J Matthew Hinkley; Kai Zou; Sanghee Park; Kristen Turner; Donghai Zheng; Joseph A Houmard Journal: Am J Physiol Endocrinol Metab Date: 2017-05-09 Impact factor: 4.310
Authors: Jill M Maples; Jeffrey J Brault; Brian M Shewchuk; Carol A Witczak; Kai Zou; Naomi Rowland; Monica J Hubal; Todd M Weber; Joseph A Houmard Journal: Physiol Genomics Date: 2015-02-10 Impact factor: 3.107