In Vivo Effects of Myocardial Creatine Depletion on Left Ventricular Function Morphology and Lipid Metabolism: Study in a Mouse Model

Lindbom, Malin; Råmunddal, Truls; Camejo, Germán; Waagstein, Finn; Ömerovic, Elmir

doi:10.1016/j.cardfail.2007.10.020

Cited by 11 publications

(9 citation statements)

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“…As in skeletal muscle, myocardial creatine, phosphocreatine, and total creatine decreased after ßGPA; an average reduction of respectively 62.4% (SD 19.3), 82.5% (SD 8.3), and 68.9% (SD 17.2) (Figure 4) [30], [35], [39], [41], [42], [47], [55], [87]–[94]. Myocardial ATP concentration decreased by 17.8% (SD 18.6) in vivo (Figure 4) and 30 to 40% (no SD available) in vitro [30], [39], [46], [47], [52], [55], [87], [88], [90], [92], [94], [95].…”

Section: Resultsmentioning

confidence: 96%

“…Wet heart weight, heart weight to body weight ratio (HW/BW), wet left ventricle weight, and left ventricle to body weight ratio were not significantly increased after ßGPA by resp. 7.3 (SD 9.6), 11.8 (SD 14.6%), 27.4 (SD 27.8), and 19.4% (SD 18.8) [16], [30], [35], [39], [41], [42], [47], [55], [58], [91], while one study reported a 25.4% decreased dry heart weight (Figure S2) [46]. Mitochondrial density was unchanged after ßGPA without visible inclusions [74], [103], but perturbations in mitochondrial form and DNA were reported in two other studies [102], [104], including cylindrically shaped mitochondria with paracrystalline inclusions with condensed and crystallized Mi-CK after in vitro incubation with ßGPA [104], and a 76% increased proliferation of left ventricle mitochondrial organelles with 22% increased mitochondrial DNA (densitometric values) [102].…”

Section: Resultsmentioning

confidence: 99%

“…During baseline performance ßGPA resulted in unchanged left ventricular systolic pressure, cardiac output, and rate of tension development, with a 69.1% reduced left ventricular end-diastolic pressure [35], but two other studies reported a 37.7% (SD18.7) reduced left ventricle fractional shortening, an echocardiographic measure of left ventricular function [41], [42]. During high workload, studies showed unchanged peak left ventricular developed pressure and cardiac output during aortic occlusion,35 a 15.7% reduced left ventricular shortening during increased pacing [41], and a reduced peak left ventricular blood pressure and heart rate (no numerical details) (Figure S2) [58].…”

Section: Resultsmentioning

confidence: 99%

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The Effect of the Creatine Analogue Beta-guanidinopropionic Acid on Energy Metabolism: A Systematic Review

2013

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BackgroundCreatine kinase plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP concentration by catalyzing the reversible transfer of the high-energy phosphate moiety (P) between creatine and ADP. Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. Therefore, we systematically reviewed the effect of beta-guanidinopropionic acid on energy metabolism and function of tissues with high energy demands.MethodsWe performed a systematic review and searched the electronic databases Pubmed, EMBASE, the Cochrane Library, and LILACS from their inception through March 2011. Furthermore, we searched the internet and explored references from textbooks and reviews.ResultsAfter applying the inclusion criteria, we retrieved 131 publications, mainly considering the effect of chronic oral administration of beta-guanidinopropionic acid (0.5 to 3.5%) on skeletal muscle, the cardiovascular system, and brain tissue in animals. Beta-guanidinopropionic acid decreased intracellular creatine and phosphocreatine in all tissues studied. In skeletal muscle, this effect induced a shift from glycolytic to oxidative metabolism, increased cellular glucose uptake and increased fatigue tolerance. In heart tissue this shift to mitochondrial metabolism was less pronounced. Myocardial contractility was modestly reduced, including a decreased ventricular developed pressure, albeit with unchanged cardiac output. In brain tissue adaptations in energy metabolism resulted in enhanced ATP stability and survival during hypoxia.ConclusionChronic beta-guanidinopropionic acid increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility. Because it is marked as safe for human use, there is a need for human data.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The Effect of the Creatine Analogue Beta-guanidinopropionic Acid on Energy Metabolism: A Systematic Review

2013

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“…β-GPA competes with creatine for cellular uptake, but is a poor substrate for CK. Chronic β-GPA feeding results in creatine depletion of between 40–87% depending on dose and length of treatment, 11, 12, 30, 31 and results in exceptionally high mortality after MI, e.g. 93% 11 to 100% 12 mortality within 24 hours.…”

Section: Discussionmentioning

confidence: 99%

Living Without Creatine

Lygate

Dawson

Hove

et al. 2013

Circulation Research

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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.

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“…This induces significant ECG changes in ST segment 7 and visible pallor on the anterior surface of the heart. Due to the large myocardial infarction, the mortality can be up to 30% 8,9 . A note should be made that infarcted myocardial area and post-MI mortality may be different among various animal strains.…”

Section: Discussionmentioning

confidence: 99%

Modified Technique for Coronary Artery Ligation in Mice

Shao

Redfors

Ömerovic

2013

JoVE

Self Cite

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Myocardial infarction (MI) is one of the most important causes of mortality in humans(1-3). In order to improve morbidity and mortality in patients with MI we need better knowledge about pathophysiology of myocardial ischemia. This knowledge may be valuable to define new therapeutic targets for innovative cardiovascular therapies(4). Experimental MI model in mice is an increasingly popular small-animal model in preclinical research in which MI is induced by means of permanent or temporary ligation of left coronary artery (LCA)(5). In this video, we describe the step-by-step method of how to induce experimental MI in mice. The animal is first anesthetized with 2% isoflurane. The unconscious mouse is then intubated and connected to a ventilator for artificial ventilation. The left chest is shaved and 1.5 cm incision along mid-axillary line is made in the skin. The left pectoralis major muscle is bluntly dissociated until the ribs are exposed. The muscle layers are pulled aside and fixed with an eyelid-retractor. After these preparations, left thoracotomy is performed between the third and fourth ribs in order to visualize the anterior surface of the heart and left lung. The proximal segment of LCA artery is then ligated with a 7-0 ethilon suture which typically induces an infarct size ~40% of left ventricle. At the end, the chest is closed and the animals receive postoperative analgesia (Temgesic, 0.3 mg/50 ml, ip). The animals are kept in a warm cage until spontaneous recovery.

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In Vivo Effects of Myocardial Creatine Depletion on Left Ventricular Function Morphology and Lipid Metabolism: Study in a Mouse Model

Cited by 11 publications

References 25 publications

The Effect of the Creatine Analogue Beta-guanidinopropionic Acid on Energy Metabolism: A Systematic Review

The Effect of the Creatine Analogue Beta-guanidinopropionic Acid on Energy Metabolism: A Systematic Review

Living Without Creatine

Modified Technique for Coronary Artery Ligation in Mice

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