Abstract
AimGuanidinoacetate N-methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT–/– mice exhibit normal exercise capacity and response to ischemic heart failure. However, we hypothesized long-term consequences of Cr deficiency and/or accumulation of the Cr precursor guanidinoacetate (GA).MethodsCardiac function and metabolic profile were studied in GAMT–/– mice >1 year.ResultsIn vivo LV catheterization revealed lower heart rate and developed pressure in aging GAMT–/– but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT–/– hearts (P < 0.001), corroborated by lower mtDNA copy number (P < 0.004), and citrate synthase activity (P < 0.05), however, without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT–/– hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signaling. This was normalized by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative.ConclusionLong-term Cr deficiency in GAMT–/– mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with hemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in aging mice.
Highlights
Creatine (Cr) is a nitrogenous organic acid derived from glycine, L-arginine and S-adenosyl-L methionine in a two-step reaction catalyzed by enzymes L-arginine:glycine amidino transferase (AGAT) in the kidney and guanidinoacetate N-methyltransferase (GAMT) in the liver (Lygate et al, 2013)
In vivo left ventricular (LV) catheterization demonstrated a hemodynamic profile in GAMT−/− consisting of lower heart rate and LV systolic pressure, reduced pressure generation with prolonged tau of isovolumetric relaxation (Figure 1)
Absolute values for these parameters were lower than observed in younger animals collected under identical experimental conditions in our laboratory [previously published in Ten Hove et al (2005b) and Lygate et al (2013)], whereas wild type (WT) values were comparable across studies
Summary
Creatine (Cr) is a nitrogenous organic acid derived from glycine, L-arginine and S-adenosyl-L methionine in a two-step reaction catalyzed by enzymes L-arginine:glycine amidino transferase (AGAT) in the kidney and guanidinoacetate N-methyltransferase (GAMT) in the liver (Lygate et al, 2013). In organs with high energy demand such as the heart, creatine is taken up by cardiomyocytes via a specific membrane transporter (CrT), whereupon it is interconverted to phosphocreatine (PCr), under the control of creatine kinase (CK) This system functions as a short-term energy buffer, maintains thermodynamically favorable levels of local reactants, and shuttles high-energy phosphates from mitochondria to sites of utilization such as the myofibril (Wyss and Kaddurah-Daouk, 2000; Ingwall and Weiss, 2004; Schlattner et al, 2006; Brosnan and Brosnan, 2007). An impaired PCr/CK system has been implicated in the pathophysiology of heart failure, with key components consistently down-regulated in both human and animal models of heart failure, regardless of etiology (Ingwall and Weiss, 2004; Ventura-Clapier et al, 2004; Lygate et al, 2007) Whether such changes have a causative role for the development of contractile dysfunction has been a matter of debate (Neubauer, 2007). Genetic loss-offunction mouse models circumvent these limitations and provide a unique approach to assess the functional significance of the PCr/CK system
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