title: Gestational diabetes is characterized by reduced mitochondrial protein expression and altered calcium signaling proteins in skeletal muscle.
abstract: The rising prevalence of gestational diabetes mellitus (GDM) affects up to 18% of pregnant women with immediate and long-term metabolic consequences for both mother and infant. Abnormal glucose uptake and lipid oxidation are hallmark features of GDM prompting us to use an exploratory proteomics approach to investigate the cellular mechanisms underlying differences in skeletal muscle metabolism between obese pregnant women with GDM (OGDM) and obese pregnant women with normal glucose tolerance (ONGT). Functional validation was performed in a second cohort of obese OGDM and ONGT pregnant women. Quantitative proteomic analysis in rectus abdominus skeletal muscle tissue collected at delivery revealed reduced protein content of mitochondrial complex I (C-I) subunits (NDUFS3, NDUFV2) and altered content of proteins involved in calcium homeostasis/signaling (calcineurin A, α1-syntrophin, annexin A4) in OGDM (n = 6) vs. ONGT (n = 6). Follow-up analyses showed reduced enzymatic activity of mitochondrial complexes C-I, C-III, and C-IV (-60-75%) in the OGDM (n = 8) compared with ONGT (n = 10) subjects, though no differences were observed for mitochondrial complex protein content. Upstream regulators of mitochondrial biogenesis and oxidative phosphorylation were not different between groups. However, AMPK phosphorylation was dramatically reduced by 75% in the OGDM women. These data suggest that GDM is associated with reduced skeletal muscle oxidative phosphorylation and disordered calcium homeostasis. These relationships deserve further attention as they may represent novel risk factors for development of GDM and may have implications on the effectiveness of physical activity interventions on both treatment strategies for GDM and for prevention of type 2 diabetes postpartum.
authors.affiliation: Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Boyle
authors.affiliation: Boston Children's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hyonson
authors.initials: H
authors.lastname: Hwang
authors.affiliation: Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Janssen
authors.affiliation: Department of Obstetrics & Gynecology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: DeVente
authors.affiliation: Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America; Department of Obstetrics and Gynecology, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Barbour
authors.affiliation: Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Teri L
authors.initials: TL
authors.lastname: Hernandez
authors.affiliation: Department of Kinesiology, Arizona State University, Tempe, Arizona, United States of America; Department of Medicine, Mayo Clinic Arizona, Tempe, Arizona, United States of America.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Mandarino
authors.affiliation: Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia; Mercy Perinatal Research Centre, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Martha
authors.initials: M
authors.lastname: Lappas
authors.affiliation: Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000328:Adult; D020013:Calcium Signaling; D016640:Diabetes, Gestational / Q000378:metabolism*; D004579:Electron Transport; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D040901:Proteomics
chemical_list: D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D000263:Adenylate Kinase