This article [Ceddia and Sweeney, 2004: (http://jp.physoc.org/cgi/reprint/555/2/409)(http://www.ncbi.nlm.nih.gov/pubmed/14724211?dopt=Abstract)] helps to shed light on the type of mechanism that could account for the cases of rhabdomyolysis in response to excessive creatine supplementation. The same mechanism, namely an increase in the phosphorylation, meaning activation, of adenosine monophosphate-activated protein kinase (AMPK) in response to exogenous creatine, could produce a U-shaped, or biphasic, dose-response to creatine supplementation in the context of neurodegenerative or psychiatric disorders. Ceddia and Sweeney (2004) found that creatine produced a decrease in the phosphocreatine to creatine (PCr/Cr) ratio but simultaneously increased the rate of glucose oxidation and decreased the rate of lactate formation that was occurring in the absence of insulin. The increase in the PCr/Cr ratio was suggested to be the "cause" of the AMPK activation, and the authors noted that the creatine pool increased more than the phosphocreatine pool (the intracellular Cr concentration was roughly twice that of the intracellular PCr concentration). There are some potential strategies that could minimize this type of effect [which is not entirely undesirable and is not harmful in and of itself (AMPK activation), given that resistance exercise produces AMPK activation in skeletal muscle cells, etc.], in my opinion, but my main point is that one would want to discuss these safety issues with one's doctor before taking creatine. Even under a doctor's supervision, it would be worthwhile to increase the dose slowly and consider limiting the dosage. Rhabdomyolysis can be life-threatening and can cause major kidney damage or kidney failure and death. I'm not commenting on any specific cases or saying that creatine routinely produces rhabdomyolysis, because I don't think it does. Most of the reports of associations discuss dosages of 20 grams/d, and that's a really high dose [(http://scholar.google.com/scholar?num=100&hl=en&lr=&q=creatine+supplement+rhabdomyolysis+OR+renal+OR+kidney); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=creatine+monohydrate+rhabdomyolysis+OR+renal+OR+kidney)].
The general idea is that this type of effect (AMPK activation) would have the potential, in my opinion, to be problematic in the context of an existing deficit in mitochondrial energy metabolism. AMPK activation doesn't always lead to neat, predictable increases in mitochondrial mass to compensate for the cellular energy deficit that produced the AMPK activation in the first place. If one is doing resistance exercise and has adapted to the training, a combination of factors tend to produce fairly reliable "trophic" effects on mitochondrial functioning in the muscle cells. But in a neurodegenerative disease or a neurological or neurodegenerative condition that is associated with inflammation or oxidative stress, creatine could simply accelerate the turnover of adenine nucleotides or inappropriately increase the rate of glucose oxidation in some cells (perhaps at the expense of other cells, etc.). If the creatine kinase enzymes are being inhibited in neurons or astrocytes in the brain, such as in response to increases in peroxynitrite formation or in nitrosative or oxidative stress in general, the magnitude of the AMPK activation could be increased. Simultaneously, the cellular response to AMPK activation could be deranged and, in my opinion, lead to problematic effects, such as maladaptive mitochondrial proliferation [discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/01/folate-cobalamin-iron-accumulation-and.html); Sebastiani et al., 2007: (http://content.onlinejacc.org/cgi/content/full/50/14/1362) (http://www.ncbi.nlm.nih.gov/pubmed/17903636)].
When one looks at the research on rhabdomyolysis, one sees that rhabdomyolysis tends to be associated with strong oxidative stress in combination with some existing deficit in oxidative metabolism. For example, reperfusion-induced rhabdomyolysis, such as can occur after some surgeries restoring blood flow to the legs, could be explained as being a result of major oxidative damage, an effect that would itself impair mitochondrial functioning, and the mitochondrial impairment that TNF-alpha and other pro-inflammatory cytokines are known to produce, via the activation of various mitogen-activated protein kinase signalling cascades. The same type of combination could account for exertional rhabdomyolysis in a person who exercises during a viral illness, etc. The point is that, although creatine can obviously produce beneficial effects on mitochondrial functioning in the long term, it is worthwhile to not assume that higher doses will produce "more" or better effects. Roitman et al. (2007) [cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/03/arginine-agmatine-and-nitric-oxide-in.html)] found that creatine at a dose of 5 grams/day was less effective as a strategy for augmenting conventional antidepressants, in some of the people in the trial, than creatine at a dose of 3 grams/d was. There's also research showing a U-shaped dose response to neuroprotection by creatine, in an animal model of Huntington's disease (one of the articles using 3-nitropropionic acid-induced neurotoxicity, I think).
The authors discuss research showing that the activation of AMPK can be increased in response to a decrease in the PCr/Cr ratio and not just in response to a decrease in the ATP/AMP ratio. The AMPK enzyme is a heterotrimer (three subunits), and there are multiple isoforms of each subunit. AMPK is regarded as a "fuel-sensing" or "glucose-sensing" enzyme that's generally activated by a decrease in ATP or, more precisely, a decrease in the ATP/AMP ratio, but other factors can activate AMPK independently of a decrease in the ATP/AMP ratio.
I don't have time to cite all the articles, but there's a whole series of articles showing that exogenous nucleotides [especially adenosine monophosphate (or intravenous inosine monophosphate, which would be expected, in my opinion, to produce effects that would be roughly more comparable to the effects of oral adenosine triphosphate or monophosphate than to the effects of oral inosine) and guanosine monophosphate, usually given in combination with some uridine or cytidine] can increase the PCr/Cr ratio or preserve the PCr/Cr ratio (and the overall PCr + Cr pool) during ischemia [(some of them are here: (http://scholar.google.com/scholar?num=100&hl=en&lr=&cites=15081505722792949318)]. Also, there's obviously a lot of research showing creatine supplementation can help to preserve the adenylate pool (adenine nucleotides, meaning AMP, ADP, & ATP) and also the adenylate charge, which is ([ATP] + 0.5 [ADP])/([ATP] + [ADP] + [AMP]) and essentially means the more high-energy adenine nucleotide pool (ATP and ADP), in various cell types [Ronca-Testoni et al., 1985: (http://www.ncbi.nlm.nih.gov/pubmed/4087306)], in vivo, during ischemia or during other conditions. I tend to think that exogenous adenosine monophosphate/triphosphate and guanosine monophosphate could produce some synergistic effects with low-dose (1-5 grams/d) creatine, under a doctor's supervision, in the context of cognitive functioning or depression or other psychiatric conditions, but that's just my opinion. Past a certain point, however, it is conceivable that high doses of creatine could derange purine metabolism, such as by increasing the export of purines from cells. Nomura et al. (2003) [Nomura et al., 2003: (http://www.nature.com/bjp/journal/v139/n4/pdf/0705316a.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/12812994)], for example, found that exogenous creatine augmented the export of ATP from endothelial cells. That effect was shown to produce anti-inflammatory effects in cultured cells (Nomura et al., 2003) but could become undesirable in other contexts, in my opinion, such as in the context of some existing deficit in energy metabolism that is impairing purine salvage, etc.
Satoh et al. (1993) [Satoh et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8173706)] discussed a really interesting mechanism to explain the increases in phosphocreatine that can occur in cells in response to exogenous purines (and pyrimidines, usually given in combination with purines in these articles). The authors' idea is basically that the ADP pool is increased and that the exogenous adenosine doesn't have to increase the ATP levels to produce an increase in the PCr/Cr ratio (Satoh et al., 1993). I think there's something to that mechanistic explanation, given that the most fundamental effect of creatine is essentially to cause an increase in the transport of ADP in and out of the mitochondria, mediated by the combined activities of mitochondrial and cytosolic creatine kinase (CK) enzymes, and thereby increase "ADP recycling" [Meyer et al., 2006: (http://www.jbc.org/cgi/reprint/281/49/37361)(http://www.ncbi.nlm.nih.gov/pubmed/17028195?dopt=Abstract)]. Ceddia and Sweeney (2004) (cited above) discussed the fact that creatine is likely to have increased the rate of glucose oxidation, in their experiments, by essentially increasing ADP transport into the mitochondria. That's an oversimplification, but that could explain the increase in the PCr/NTP levels, measured by MRS, found in the brains of humans given supplemental S-adenosylmethionine (SAM-e) [Silveri et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/14550683)]. NTP refers to the pool of beta-nucleotide triphosphates and is mostly thought to reflect the size of the ATP pool. In my opinion, that effect on phosphocreatine by SAM-e was not primarily produced by an increase in guanidinoacetate N-methyltransferase activity but was the result of an increase in the adenylate and purine nucleotide pools in neurons and astroyctes, etc. Other authors have discussed the possibility that the effects of SAM-e on depression are mediated by increases in adenosine (or its "metabolites," etc.), and I've cited that type of thing in past postings. I think that's the case, and, in my opinion, the use of adenosine monophosphate and guanosine monophosphate would be superior to the use of most of the presently-available formulations of SAM-e for any purpose that SAM-e has been used for. Another possibility is that adenosine could act as a mild anticonvulsant and limit the PCr depletion that can result from excessive, excitatory glutamatergic transmission in the brain.
One strategy for maintaining creatine kinase activity would, in my opinion, be the maintenance of the serum uric acid (urate) in the high-normal range. Urate scavenges peroxynitrite and can protect against the cellular energy deficits in myocardial tissue, following ischemia, and the effect may be due to the protection by urate against the nitrosylative inactivation of CK by peroxynitrite (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=peroxynitrite+%22creatine+kinase%22) or nitric oxide, as discussed by Xie et al. (1998) [Xie et al., 1998: (http://circres.ahajournals.org/cgi/reprint/82/8/891)(http://www.ncbi.nlm.nih.gov/pubmed/9576108?dopt=Abstract)]. Relatively low doses of adenosine or guanosine would accomplish that elevation of urate. That's a reason one would want to measure one's uric acid levels, under the supervision of a doctor. Methylcobalamin can lower methylmalonic acid (MMA) levels, and MMA and its associated "metabolites" (methylcitric acid, etc.) can produce inhibition of creatine kinase activity (http://scholar.google.com/scholar?q=methylmalonic+%22creatine+kinase%22&hl=en&lr=). Magnesium is a major factor that influences both the activity and Keq of creatine kinase enzymes, in a manner that tends to increase the PCr/Cr ratio at equilibrium (that ratio is a reflection of the Keq values for the reversible creatine kinase enzymatic reactions) (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=magnesium+%22creatine+kinase%22).
No comments:
Post a Comment