Language:
English
In:
Journal of Physiology, Jan, 2013, Vol.591, p.571(22)
Description:
To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2012.241760/abstract Byline: C. I. Nabuurs(1), C. U. Choe(2)(3), A. Veltien(1), H. E. Kan(1), L. J. C. van Loon(4), R. J. T. Rodenburg(5), J. Matschke(6), B. Wieringa(7), G. J. Kemp(8), D. Isbrandt(2), A. Heerschap(1) Key points Creatine (Cr) plays an important role in muscle energy homeostasis as a substrate in the creatine kinase phosphoryl exchange reaction, but the consequences of creatine depletion are incompletely understood. We assessed the morphological, metabolic and functional consequences of systemic creatine depletion on skeletal muscle in a mouse model with deficiency of an essential enzyme in the biosynthesis of creatine (AGAT.sub.-/- mice). We show that Cr depletion leads to several metabolic abnormalities in muscle, including reduced ATP, increased inorganic phosphate levels and reduced activities of proton-pumping respiratory chain enzymes and an elevated glycolytic contribution in ischaemic circumstances. The Cr-depleted muscle suffers from reduced grip strength, severe atrophy and abnormal mitochondrial structures, increased overall mitochondrial content and an increased number of lipid droplets. 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.sub.-/- mice can be switched between Cr deficient and normal simply by dietary manipulation. 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.sub.-/-), 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.sub.-/- mice. Compared with wild-type, the inorganic phosphate/[beta]-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain enzymes were reduced, whereas F.sub.1F.sub.0-ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT.sub.-/- 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.sub.-/- 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.sub.-/- 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. Author Affiliation: (1)Radiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands (2)Experimental Neuropediatrics, Center for Molecular Neurobiology Hamburg Zentrum fur Molekular Neurobiologie Hamburg and Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (3)Neurology (6)Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (4)Department of Human Movement Sciences, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands (5)Department of Pediatrics (7)Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands (8)Department of Musculoskeletal Biology & Magnetic Resonance and Image Analysis Research Centre, University of Liverpool, Liverpool, UK Correspondence: (*) A. Heerschap: Department of Radiology 667, Geert Grooteplein 10, 6500HB Nijmegen, The Netherlands. Email: a.heerschap@rad.umcn.nl Article Note: C. I. Nabuurs and C. U. Choe contributed equally to this work. (Received 26 July 2012; accepted after revision 30 October 2012; first published online 5 November 2012) CAPTION(S): Supporting info item Supporting info item Supporting info item Supporting info item Supporting info item Supporting info item
Keywords:
Creatine -- Physiological Aspects
ISSN:
0022-3751
Source:
Cengage Learning, Inc.
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