title: Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake.
abstract: Creatine (Cr) plays an important role in muscle energy homeostasis by its participation in the ATP-phosphocreatine phosphoryl exchange reaction mediated by creatine kinase. Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of l-arginine:glycine amidinotransferase (AGAT(-/-)), which catalyses the first step of Cr biosynthesis. In vivo magnetic resonance spectroscopy showed a near-complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT(-/-) mice. Compared with wild-type, the inorganic phosphate/β-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain enzymes were reduced, whereas F(1)F(0)-ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT(-/-) mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT(-/-) muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT(-/-) mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle-specific creatine kinase deficiency, which suggests a multifaceted involvement of creatine in muscle energy homeostasis in addition to its role in the phosphocreatine-creatine kinase system.
authors.affiliation: Radiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: C I
authors.initials: CI
authors.lastname: Nabuurs
authors.forename: C U
authors.initials: CU
authors.lastname: Choe
authors.forename: A
authors.initials: A
authors.lastname: Veltien
authors.forename: H E
authors.initials: HE
authors.lastname: Kan
authors.forename: L J C
authors.initials: LJ
authors.lastname: van Loon
authors.forename: R J T
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: J
authors.initials: J
authors.lastname: Matschke
authors.forename: B
authors.initials: B
authors.lastname: Wieringa
authors.forename: G J
authors.initials: GJ
authors.lastname: Kemp
authors.forename: D
authors.initials: D
authors.lastname: Isbrandt
authors.forename: A
authors.initials: A
authors.lastname: Heerschap
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000579:Amidinotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D003401:Creatine / Q000172:deficiency* / Q000627:therapeutic use; D003402:Creatine Kinase / Q000378:metabolism; D002658:Developmental Disabilities / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004734:Energy Metabolism; D018737:Hand Strength; D006614:Hindlimb / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D008607:Intellectual Disability / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007511:Ischemia / Q000378:metabolism; D050356:Lipid Metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics*; D010710:Phosphates / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D013064:Speech Disorders / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
chemical_list: D010710:Phosphates; D000255:Adenosine Triphosphate; D000579:Amidinotransferases; C020681:glycine amidinotransferase; D003402:Creatine Kinase; D006180:Proton-Translocating ATPases; D003401:Creatine