title: Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD.
abstract: Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter. MSUD is an orphan disease with a need for novel drug interventions. Here using a 96-well plate (liquid chromatography- mass spectrometry (LC-MS) based drug-screening platform we show that Metformin, a widely used anti-diabetic drug, reduces levels of KIC in patient-derived fibroblasts by 20-50%. This Metformin-mediated effect was conserved in vivo; Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice, and restored levels of mitochondrial metabolites (e.g. AMP and other TCA). The drug also decreased the expression of mitochondrial branched chain amino transferase (BCAT) which produces KIC in skeletal muscle. This suggests that Metformin can restore skeletal muscle homeostasis in MSUD by decreasing mitochondrial KIC production.
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.
authors.forename: Davis
authors.initials: D
authors.lastname: S Sonnet
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.|University of Michigan, Department of Pathology, 1150 W Medical Center Dr #7520, Ann Arbor, MI 48109, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: N O'Leary
authors.affiliation: University of Colorado, Denver Anschutz Medical Campus 13001 E. 17th Pl. Aurora, Colorado, 80045, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: A Gutierrez
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: M Nguyen
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.
authors.forename: Samiha
authors.initials: S
authors.lastname: Mateen
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.
authors.forename: Yuehmei
authors.initials: Y
authors.lastname: Hsu
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.
authors.forename: Kylie
authors.initials: K
authors.lastname: P Mitchell
authors.affiliation: University of California, Davis 1 Shields Ave, Davis, CA 95616, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: J Lopez
authors.affiliation: University of Pittsburgh School of Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 153224.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: K Kennedy
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Ramanathan
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000097:blood*; D000818:Animals; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006706:Homeostasis; D006720:Homozygote; D007651:Keto Acids / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D007662:Ketosis / Q000097:blood*; D007930:Leucine / Q000378:metabolism; D008297:Male; D008375:Maple Syrup Urine Disease / Q000097:blood*; D013058:Mass Spectrometry; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation
chemical_list: D000597:Amino Acids, Branched-Chain; D007651:Keto Acids; D007656:Ketoglutaric Acids; C013082:alpha-ketoisocaproic acid; D008687:Metformin; D007930:Leucine