Living Without Creatine

Abstract

Rationale Creatine is thought to be involved in the spatial and temporal buffering of ATP in energetic organs such as heart and skeletal muscle. Creatine depletion affects force generation during maximal stimulation, while reduced levels of myocardial creatine are a hallmark of the failing heart, leading to the widely held view that creatine is important at high workloads and under conditions of pathological stress. Objective We therefore hypothesised that the consequences of creatine-deficiency in mice would be impaired running capacity, and exacerbation of heart failure following myocardial infarction. Methods and Results Surprisingly, mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase – GAMT) voluntarily ran just as fast and as far as controls (>10km/night) and performed the same level of work when tested to exhaustion on a treadmill. Furthermore, survival following myocardial infarction was not altered, nor was subsequent LV remodelling and development of chronic heart failure exacerbated, as measured by 3D-echocardiography and invasive hemodynamics. These findings could not be accounted for by compensatory adaptations, with no differences detected between WT and GAMT−/− proteomes. Alternative phosphotransfer mechanisms were explored; adenylate kinase activity was unaltered, and although GAMT−/− hearts accumulated the creatine pre-cursor guanidinoacetate, this had negligible energy-transfer activity, while mitochondria retained near normal function. Conclusions Creatine-deficient mice show unaltered maximal exercise capacity and response to chronic myocardial infarction, and no obvious metabolic adaptations. Our results question the paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle.

Creatine: a miserable life without it

“…Since the accumulated P-GAA levels are generally high in GAMT knockout animals, it is likely that the relatively mild phenotype in terms of skeletal and cardiac muscle performance can be explained by this fact. Thus, the results described above do not justify the conclusions taken by Lygate et al (2013), specifically in light of the fact that reduced PCr concentrations and PCr/ATP ratios, as well as a reduced flux through the CK reaction, have been consistently seen in human myocardial infarction (Bottomley et al 2009). Zervou et al (2016) show in an elegant study that mice over-expressing the creatine transporter (CrT), and thus displaying elevated cardiac total creatine levels, were protected against ischemia/reperfusion injury via improved energy reserves.…”

“…In their earlier provocative work entitled "Living without creatine", Lygate et al (2013) showed that transgenic mice without GAMT voluntarily ran as fast and performed the same level of work when tested to exhaustion on a treadmill, and additionally, that their survival following myocardial infarction was not altered in comparison to wild-type animals. Based on these results, the authors questioned the long-held paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle.…”

“…It is well known that P-GAA can still serve, albeit less efficiently than PCr, as a substrate for the CK reaction to replenish ATP from P-GAA (Boehm et al 1996). Although Lygate et al (2013), using 31 P-NMR saturation transfer measurements, were apparently unable to show a phosphoryl-transfer from the energy-rich P-GAA to ADP to give ATP in cardiac muscle, this had been shown earlier to take place in vivo, at least in skeletal muscle (Kan et al 2004). There is no apparent explanation as to why this would not also happen in cardiac muscle, where a clearly discernible P-GAA peak was visible.…”

“…So, then, living without creatine (Lygate et al 2013) is not an option. Who would want to live with severe muscular atrophy, neuromuscular and neurological impairments, developmental speech delay, epileptic seizures, autism and brain atrophy, shivering due to lack of thermoregulation, as well as troubled fertility and reproduction, auditory hearing and sense of equilibrium, and many more?…”

Probiotic Administration Attenuates Myocardial Hypertrophy and Heart Failure After Myocardial Infarction in the Rat

“…21 However, creatine deficiency produced by deletion of the biosynthetic enzyme guanidinoacetate N-methyltransferase failed to exert any effect on postinfarction survival or LV remodeling and dysfunction after CAL. 22 Thus, at present, the functional significance of creatine in the failing myocardium and its preservation by probiotic administration is difficult to appreciate particularly as this relates to postinfarction remodeling and the evolution to heart failure.…”