Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT−/− mice

Malte Stockebrand, Ali Sasani Nejad, Axel Neu, Kusum Kharbanda, Kathrin Sauter, Stefan Schillemeit, Dirk Isbrandt, Chi un Choe

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Skeletal muscles require energy either at constant low (e.g., standing and posture) or immediate high rates (e.g., exercise). To fulfill these requirements, myocytes utilize the phosphocreatine (PCr)/creatine (Cr) system as a fast energy buffer and shuttle. We have generated mice lacking l-arginine:glycine amidino transferase (AGAT), the first enzyme of creatine biosynthesis. These AGAT−/− (d/d) mice are devoid of the PCr/Cr system and reveal severely altered oxidative phosphorylation. In addition, they exhibit complete resistance to diet-induced obesity, which is associated with a chronic activation of AMP-activated protein kinase in muscle and white adipose tissue. The underlying metabolic rearrangements have not yet been further analyzed. Here, we performed gene expression analysis in skeletal muscle and a serum amino acid profile of d/d mice revealing transcriptomic and metabolic alterations in pyruvate and glucose pathways. Differential pyruvate tolerance tests demonstrated preferential conversion of pyruvate to alanine, which was supported by increased protein levels of enzymes involved in pyruvate and alanine metabolism. Pyruvate tolerance tests suggested severely impaired hepatic gluconeogenesis despite increased availability of pyruvate and alanine. Furthermore, enzymes of serine production and one-carbon metabolism were significantly up-regulated in d/d mice, indicating increased de novo formation of one-carbon units from carbohydrate metabolism linked to NAD(P)H production. Besides the well-established function of the PCr/Cr system in energy metabolism, our transcriptomic and metabolic analyses suggest that it plays a pivotal role in systemic one-carbon metabolism, oxidation/reduction, and biosynthetic processes. Therefore, the PCr/Cr system is not only an energy buffer and shuttle, but also a crucial component involved in numerous systemic metabolic processes.

Original languageEnglish (US)
Pages (from-to)2025-2039
Number of pages15
JournalAmino Acids
Volume48
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Salvaging
Creatine
Transferases
Pyruvic Acid
Glycine
Arginine
Phosphocreatine
Metabolism
Alanine
Muscle
Carbon
Buffers
Skeletal Muscle
Enzymes
White Adipose Tissue
AMP-Activated Protein Kinases
Gluconeogenesis
Biosynthesis
Oxidative Phosphorylation
Carbohydrate Metabolism

Keywords

  • Alanine
  • Arginine:glycine amidinotransferase (AGAT)
  • Creatine
  • Glucose
  • Pyruvate
  • Skeletal muscle

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Stockebrand, M., Nejad, A. S., Neu, A., Kharbanda, K., Sauter, K., Schillemeit, S., ... Choe, C. U. (2016). Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT−/− mice. Amino Acids, 48(8), 2025-2039. https://doi.org/10.1007/s00726-016-2202-7

Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT−/− mice. / Stockebrand, Malte; Nejad, Ali Sasani; Neu, Axel; Kharbanda, Kusum; Sauter, Kathrin; Schillemeit, Stefan; Isbrandt, Dirk; Choe, Chi un.

In: Amino Acids, Vol. 48, No. 8, 01.08.2016, p. 2025-2039.

Research output: Contribution to journalArticle

Stockebrand, M, Nejad, AS, Neu, A, Kharbanda, K, Sauter, K, Schillemeit, S, Isbrandt, D & Choe, CU 2016, 'Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT−/− mice', Amino Acids, vol. 48, no. 8, pp. 2025-2039. https://doi.org/10.1007/s00726-016-2202-7
Stockebrand, Malte ; Nejad, Ali Sasani ; Neu, Axel ; Kharbanda, Kusum ; Sauter, Kathrin ; Schillemeit, Stefan ; Isbrandt, Dirk ; Choe, Chi un. / Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT−/− mice. In: Amino Acids. 2016 ; Vol. 48, No. 8. pp. 2025-2039.
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AU - Stockebrand, Malte

AU - Nejad, Ali Sasani

AU - Neu, Axel

AU - Kharbanda, Kusum

AU - Sauter, Kathrin

AU - Schillemeit, Stefan

AU - Isbrandt, Dirk

AU - Choe, Chi un

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KW - Glucose

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