GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function

Horváth, Tamas L.; Erion, Derek M.; Elsworth, John D.; Roth, Robert H.; Shulman, Gerald I.; Andrews, Zane B.

doi:10.1016/j.nbd.2011.03.005

Cited by 24 publications

(27 citation statements)

References 67 publications

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“…These studies showed an average weight decrease of 10.1% (SD 7.6) (Figure 2). In five studies with numerical information on ad libitum food intake, there was no evidence of reduced food intake (data not shown) [12], [20], [35], [56], [60]. One study proposed weight loss due a central hypophagic effect, showing that ßGPA (single intrathecal injection) resulted in a 9-fold increased Fos expression, a measure of hypothalamus activity, in rats [61].…”

Section: Resultsmentioning

confidence: 98%

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: 98%

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

2013

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“…In Tsc2 -/-MEFs cells, cell growth is controlled by AMPK activation and results in the direct phosphorylation of Raptor of mTORC1 (29,30). AMPK directly phosphorylates the ULK1 complex (31)(32)(33)(34).…”

Section: Upstream and Downstream Deleted Of Ampk Signaling Pathwaysmentioning

confidence: 99%

AMP-activated protein kinase: implications on ischemic diseases

Ahn¹,

Kim²,

Lim³

et al. 2012

BMB Reports

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Ischemia is a blockage of blood supply due to an embolism or a hemorrhage in a blood vessel. When an organ cannot receive oxygenated blood and can therefore no longer replenish its blood supply due to ischemia, stresses, such as the disruption of blood glucose homeostasis, hypoglycemia and hypoxia, activate the AMPK complex. LKB1 and CaMKKβ are essential activators of the AMPK signaling pathway. AMPK triggers proangiogenic effects through the eNOS protein in tissues with ischemic conditions, where cells are vulnerable to apoptosis, autophagy and necrosis. The AMPK complex acts to restore blood glucose levels and ATP levels back to homeostasis. This review will discuss AMPK, as well as its key activators (LKB1 and CaMKKβ), as a central energy regulator and evaluate the upstream and downstream regulating pathways of AMPK. We will also discuss how we can control this important enzyme in ischemic conditions to prevent harmful effects in patients with vascular damage. [BMB Reports 2012; 45(9): 489-495]

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“…Acute loss of Cr using pharmacological agents that block the CrT in the heart leads to mitochondrial impairment and, ultimately, insufficient ATP to carry out normal cellular processes, suggesting perturbed energy metabolism in CTD (O'Gorman et al 1996). Interestingly, GPA administration increased mitochondrial density in the striatum of mice (Horvath et al 2011). …”

Section: Introductionmentioning

confidence: 99%

Creatine transporter deficiency leads to increased whole body and cellular metabolism

et al. 2016

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Creatine (Cr) is a guanidino compound required for rapid replenishment of ATP in cells with a high-energy demand. In humans, mutations in the Cr transporter (CRT;SLC6A8) prevent Cr entry into tissue and result in significant intellectual impairment, epilepsy, and aphasia. The lack of Cr on both whole body and cellular metabolism was evaluated in Crt knockout (Crt−/y) mice, a high-fidelity model of human CRT deficiency. Crt−/y mice have reduced body mass however show a two-fold increase in body fat. There was increased energy expenditure in a homecage environment and during treadmill running in Crt−/y mice. Consistent with the increases in whole-body metabolic function, Crt−/y mice show increases in cellular metabolism as well. Mitochondrial respiration increased in skeletal muscle fibers and hippocampal lysates from Crt−/y mice. In addition, Crt−/y mice had increased citrate synthase activity, suggesting a higher number of mitochondria instead of an increase in mitochondrial activity. In order to determine if the increase in respiration was due to increased mitochondrial numbers, we measured oxygen consumption in an equal number of mitochondria from Crt+/y and Crt−/y mice. There were no changes in mitochondrial respiration when normalized to mitochondrial number, suggesting that the increase in respiration observed could be to higher mitochondrial content in Crt−/y mice.

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GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function

Cited by 24 publications

References 67 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

AMP-activated protein kinase: implications on ischemic diseases

Creatine transporter deficiency leads to increased whole body and cellular metabolism

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