Stockebrand, Malte, Nejad, Ali Sasani, Neu, Axel ORCID: 0000-0001-7045-7194, Kharbanda, Kusum K., Sauter, Kathrin, Schillemeit, Stefan, Isbrandt, Dirk and Choe, Chi-un (2016). Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT(-/-) mice. Amino Acids, 48 (8). S. 2025 - 2040. WIEN: SPRINGER WIEN. ISSN 1438-2199

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Stockebrand, MalteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nejad, Ali SasaniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neu, AxelUNSPECIFIEDorcid.org/0000-0001-7045-7194UNSPECIFIED
Kharbanda, Kusum K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sauter, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schillemeit, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isbrandt, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Choe, Chi-unUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-268017
DOI: 10.1007/s00726-016-2202-7
Journal or Publication Title: Amino Acids
Volume: 48
Number: 8
Page Range: S. 2025 - 2040
Date: 2016
Publisher: SPRINGER WIEN
Place of Publication: WIEN
ISSN: 1438-2199
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SKELETAL-MUSCLE; ENERGY-METABOLISM; AMPK; GLUCONEOGENESIS; AMIDINOTRANSFERASE; EXPENDITURE; ACTIVATION; ADAPTATION; RECEPTOR; CAPACITYMultiple languages
Biochemistry & Molecular BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26801

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