Transcriptomic and metabolic analyses reveal salvage pathways in creatine-deficient AGAT(-/-) mice
| Autor: | Chi un Choe, Kusum K. Kharbanda, Malte Stockebrand, Stefan Schillemeit, Axel Neu, Ali Sasani Nejad, Kathrin Sauter, Dirk Isbrandt |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
metabolism [Amidinotransferases] Amidinotransferases metabolism [Muscle Skeletal] Phosphocreatine Developmental Disabilities Clinical Biochemistry chemically induced [Obesity] Biochemistry Oxidative Phosphorylation pathology [Muscle Skeletal] chemistry.chemical_compound Mice 0302 clinical medicine genetics [Obesity] pathology [Speech Disorders] genetics [Phosphocreatine] Alanine chemistry.chemical_classification Mice Knockout pathology [Adipose Tissue White] metabolism [Phosphocreatine] metabolism [Intellectual Disability] genetics [Developmental Disabilities] ddc:540 genetics [Amidinotransferases] Metabolome pathology [Amino Acid Metabolism Inborn Errors] Pyruvate dehydrogenase kinase pathology [Obesity] Adipose Tissue White Biology Carbohydrate metabolism Creatine Speech Disorders pathology [Intellectual Disability] 03 medical and health sciences genetics [Speech Disorders] genetics [Amino Acid Metabolism Inborn Errors] Intellectual Disability metabolism [Obesity] glycine amidinotransferase Animals Obesity Protein kinase A Muscle Skeletal Amino Acid Metabolism Inborn Errors metabolism [Developmental Disabilities] metabolism [Adipose Tissue White] deficiency [Amidinotransferases] Organic Chemistry Metabolism metabolism [Amino Acid Metabolism Inborn Errors] metabolism [Speech Disorders] pathology [Developmental Disabilities] 030104 developmental biology Enzyme chemistry genetics [Intellectual Disability] Transcriptome 030217 neurology & neurosurgery Arginine-Glycine Amidinotransferase Deficiency |
| Zdroj: | Amino acids 48(8), 2025-2039 (2016). doi:10.1007/s00726-016-2202-7 |
| DOI: | 10.1007/s00726-016-2202-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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