Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake.

C I Nabuurs; Chi-Un Choe; A Veltien; H E Kan; L J C van Loon; R J T Rodenburg; Jakob Matschke; B Wieringa; G J Kemp; Dirk Isbrandt; A Heerschap

Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake.

Standard

Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake. / Nabuurs, C I; Choe, Chi-Un; Veltien, A; Kan, H E; van Loon, L J C; Rodenburg, R J T; Matschke, Jakob; Wieringa, B; Kemp, G J; Isbrandt, Dirk; Heerschap, A.

In: J PHYSIOL-LONDON, Vol. 591, No. Pt 2, Pt 2, 2013, p. 571-592.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Nabuurs, CI, Choe, C-U, Veltien, A, Kan, HE, van Loon, LJC, Rodenburg, RJT, Matschke, J, Wieringa, B, Kemp, GJ, Isbrandt, D & Heerschap, A 2013, 'Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake.', J PHYSIOL-LONDON, vol. 591, no. Pt 2, Pt 2, pp. 571-592. <http://www.ncbi.nlm.nih.gov/pubmed/23129796?dopt=Citation>

APA

Nabuurs, C. I., Choe, C-U., Veltien, A., Kan, H. E., van Loon, L. J. C., Rodenburg, R. J. T., Matschke, J., Wieringa, B., Kemp, G. J., Isbrandt, D., & Heerschap, A. (2013). Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake. J PHYSIOL-LONDON, 591(Pt 2), 571-592. [Pt 2]. http://www.ncbi.nlm.nih.gov/pubmed/23129796?dopt=Citation

Vancouver

Nabuurs CI, Choe C-U, Veltien A, Kan HE, van Loon LJC, Rodenburg RJT et al. Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake. J PHYSIOL-LONDON. 2013;591(Pt 2):571-592. Pt 2.

Bibtex

@article{b25e04af1052448381dcf4d793dc4063,

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/?-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.",

keywords = "Animals, Mice, Mice, Knockout, Lipid Metabolism, Magnetic Resonance Spectroscopy, Hydrogen-Ion Concentration, Adenosine Triphosphate/metabolism, *Energy Metabolism, Amidinotransferases/deficiency/genetics/metabolism, Amino Acid Metabolism, Inborn Errors/diet therapy/metabolism/pathology/*physiopathology, Creatine/*deficiency/therapeutic use, Creatine Kinase/metabolism, Developmental Disabilities/diet therapy/metabolism/pathology/physiopathology, Hand Strength, Hindlimb/pathology, Intellectual Disability/diet therapy/metabolism/pathology/*physiopathology, Ischemia/metabolism, Mitochondria/metabolism/ultrastructure, Muscle Fibers, Skeletal/metabolism/pathology, Muscle, Skeletal/metabolism/pathology/physiopathology, Muscular Atrophy/*genetics, Phosphates/metabolism, Proton-Translocating ATPases/metabolism, Speech Disorders/diet therapy/metabolism/pathology/*physiopathology, Animals, Mice, Mice, Knockout, Lipid Metabolism, Magnetic Resonance Spectroscopy, Hydrogen-Ion Concentration, Adenosine Triphosphate/metabolism, *Energy Metabolism, Amidinotransferases/deficiency/genetics/metabolism, Amino Acid Metabolism, Inborn Errors/diet therapy/metabolism/pathology/*physiopathology, Creatine/*deficiency/therapeutic use, Creatine Kinase/metabolism, Developmental Disabilities/diet therapy/metabolism/pathology/physiopathology, Hand Strength, Hindlimb/pathology, Intellectual Disability/diet therapy/metabolism/pathology/*physiopathology, Ischemia/metabolism, Mitochondria/metabolism/ultrastructure, Muscle Fibers, Skeletal/metabolism/pathology, Muscle, Skeletal/metabolism/pathology/physiopathology, Muscular Atrophy/*genetics, Phosphates/metabolism, Proton-Translocating ATPases/metabolism, Speech Disorders/diet therapy/metabolism/pathology/*physiopathology",

author = "Nabuurs, {C I} and Chi-Un Choe and A Veltien and Kan, {H E} and {van Loon}, {L J C} and Rodenburg, {R J T} and Jakob Matschke and B Wieringa and Kemp, {G J} and Dirk Isbrandt and A Heerschap",

year = "2013",

language = "English",

volume = "591",

pages = "571--592",

journal = "J PHYSIOL-LONDON",

issn = "0022-3751",

publisher = "Wiley-Blackwell",

number = "Pt 2",

}

RIS

TY - JOUR

T1 - Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake.

AU - Nabuurs, C I

AU - Choe, Chi-Un

AU - Veltien, A

AU - Kan, H E

AU - van Loon, L J C

AU - Rodenburg, R J T

AU - Matschke, Jakob

AU - Wieringa, B

AU - Kemp, G J

AU - Isbrandt, Dirk

AU - Heerschap, A

PY - 2013

Y1 - 2013

N2 - 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/?-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.

AB - 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/?-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.

KW - Animals

KW - Mice

KW - Mice, Knockout

KW - Lipid Metabolism

KW - Magnetic Resonance Spectroscopy

KW - Hydrogen-Ion Concentration

KW - Adenosine Triphosphate/metabolism

KW - Energy Metabolism

KW - Amidinotransferases/deficiency/genetics/metabolism

KW - Amino Acid Metabolism, Inborn Errors/diet therapy/metabolism/pathology/physiopathology

KW - Creatine/deficiency/therapeutic use

KW - Creatine Kinase/metabolism

KW - Developmental Disabilities/diet therapy/metabolism/pathology/physiopathology

KW - Hand Strength

KW - Hindlimb/pathology

KW - Intellectual Disability/diet therapy/metabolism/pathology/physiopathology

KW - Ischemia/metabolism

KW - Mitochondria/metabolism/ultrastructure

KW - Muscle Fibers, Skeletal/metabolism/pathology

KW - Muscle, Skeletal/metabolism/pathology/physiopathology

KW - Muscular Atrophy/genetics

KW - Phosphates/metabolism

KW - Proton-Translocating ATPases/metabolism

KW - Speech Disorders/diet therapy/metabolism/pathology/physiopathology