Article: Missing Protein and Excercise Inability

leela

Slow But Hopeful
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Interesting implications for PWCs:
http://www.sciencedaily.com/releases/2010/11/101130122033.htm

Couch Potato Effect: Missing Protein Leaves Mice Unable to Exercise
ScienceDaily (Nov. 30, 2010)

Daniel Kelly, M.D., and his colleagues at Sanford-Burnham Medical Research Institute (Sanford-Burnham) at Lake Nona have unveiled a surprising new model for studying muscle function: the couch potato mouse. While these mice maintain normal activity and body weight, they do not have the energy to exercise. In the December 1 issue of Cell Metabolism, Dr. Kelly's team reports what happens when muscle tissue lacks PGC-1, a protein coactivator that muscles need to convert fuel into energy.

"Part of our interest in understanding the factors that allow muscles to exercise is the knowledge that whatever this machinery is, it becomes inactive in obesity, aging, diabetes and other chronic conditions that affect mobility," Dr. Kelly explained.

Normally, physical stimulation boosts PGC-1 activity in muscle cells, which switches on genes that increase fuel storage, ultimately leading to "trained" muscle (the physical condition most people hope to attain through exercise). In obese individuals, PGC-1 levels drop, possibly further reducing a person's capacity to exercise -- creating a vicious cycle. In this study, mice without muscle PGC-1 looked normal and walked around without difficulty, but could not run on a treadmill.
This is the first time that PGC-1 has been completely removed from muscle tissue, providing researchers with a new model to unravel the protein's role in muscle development, exercise and metabolism. So what happens to mice with muscles short on PGC-1? Their mitochondria -- the part of the cell that converts fuel into energy -- can't function properly, so cells have to work harder to stay vigorous. This extra effort rapidly depletes carbohydrate fuel stores, leading to premature fatigue. In short, PGC-1 is necessary for exercise, but not normal muscle development and activity.

But these mice held another surprise. PGC-1-deficient couch potato mice were not obese and still respond normally to insulin -- meaning they are not at risk for developing diabetes despite their sedentary lifestyles and mitochondrial problems. This was unexpected because many scientists believe that dysfunctional mitochondria trigger a cascade of insulin resistance and diabetes. This study dispels that notion, instead suggesting that perhaps malfunctioning mitochondria are a result of
diabetes, rather than a cause.

"Lo and behold, even though these animals couldn't run, they showed no evidence of insulin resistance," Dr. Kelly said. "We are now investigating what happens when we boost PGC-1 activity intermittently, as normally occurs when a person exercises."
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung and Blood Institute (NHLBI), institutes within the National Institutes of Health (NIH), and the American Diabetes Association.
 

George

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Can I have the PGC-1 they took out of the mice, please? (big grins) This is a great study though and hopefully lab A is talking to lab B and someone will look at this in the ME/CFS community.
 

pictureofhealth

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I sent a copy to ME Research UK (real scientists!) in Scotland, in case it is of interest to them. They fund muscle function and vascular studies and all kinds of ME research. They are also good at communicating with patients.
 
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The only mention of PGC-1 in a CFS paper that I've found so far:

http://www.ncbi.nlm.nih.gov/pubmed/18684570

The paper is not that well written. The first half it reads like a rushed, slighly plagiarized summary of a UK CFS Review article. On the other hand, perhaps it is written like that so that certain UK people actually pay attention.

The hypothesis is somewhat interesting though.

William Banes said:
RAS, alarm response and CFS

A common (although not obvious) theme running through CFS is the involvement of the body’s ‘fight or flight’ systems, and particularly the neurotransmitters and hormones of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). Several indirect lines of evidence suggests that low RAS activation is related causally linked to CFS triggering or maintenance.

• Serum Angiotensin converting enzyme (ACE) is recognised as a marker for CFS
[65].

• Gulf war veterans with the Tissue ACE gene I allele (high level expression) are less likely to be found to develop CFS as part of the ‘Gulf War Syndrome’ spectrum of disorders than veterans who carry the D allele. DD veterans are 8 times as likely to suffer chronic fatigue as the whole population [66].

• Chronic heart failure is often accompanied by CFS-like fatigue (which is not designated CFS because of the co-morbidity with heart failure). Haemodynamic parameters do not explain this. The principle difference between the two patient sets is the extensive dosing of heart failure patients with AT-II inhibitors, beta blockers and ACE inhibitors, usually in combination [12].

• Vasopressin levels have been reported to be lower in CFS patients, suggesting relative inactivity of all blood pressure control systems [67].

• Oxygen delivery to muscles post exercise has been found to be reduced in CFS, which has been attributed to reduced autonomic control of vasodilation in CFS [62].

RAS, SNS and mitochondria

A mechanism for the effect of the RAS on fatigue is through mitochondrial efficiency and energy reserve. Several pieces of evidence suggest that RAS and SNS activation reduce the efficiency of mitochondrial energy production, and increase mitochondrial number.

• Beta-3 agonist induce UCP-1, through mechanism involving rB protein, in fat (turning white to brown fat) [68] and [69] and muscle [70]. Beta adrenorecetopr knockouts depress brown fat formation [71]. The same pathways stimulate Mitochondrial biogenesis via CaMK and PGC-1 [72].

• AT-II antagonists increase the duration and energy of sperm swimming. Sperm are almost totally dependent on mitochondrial metabolism of externally supplied sugars for their energy. AT-II antagonists increase this power generation, ie increase the efficiency with which the sperm generate energy. [73] and [74].

• RAS blockade is associated with increased ability to build muscle mass. There are several pieces of evidence of this type, from cachexic patients, training athletes and high altitude moutaineers [75], [76] and [77]. This may seem a contrary piece of evidence. However, any body builder knows that muscle mass is best increased through intense anaerobic exercise, not through aerobic exercise. If RAS blockade reduces the ability of mitochondria to upregulate their energy generation, then a given level of activity would exhaust the aerobic energy generation capacity of low-RAS individuals before it exhausted the aerobic capacity of high-RAS individuals.

Consistent with this hypothesis (but with many others as well) is that CFS symptoms are increasingly being shown to be associated with, and possibly caused by, increased oxidative stress [78], which would be expected of long-term loss of adequate mitochondrial function as other systems took up the task of balancing muscle redox balance [79] and [80].

RAS, SNS and mitochondrial responsiveness in CFS

Why should the same hormonal system increase mitochondrial number yet decrease mitochondrial efficiency? I hypothesise that this is due to an inverse correlation between mitochondrial efficiency and the ability of mitochondria to increase energy output on demand, and that this links the same systems to CFS.

For rapid response to shock or stress (such as caused by psychological shock, such as activates the SNS, or haemodynamic shock such as activates the RAS), mitochondrial energy production must be capable of being upregulated in seconds. One of the more common ways of enabling metabolic pathways to respond rapidly to changes in control, and to provide greater response than feedback inhibition and substrate activation mechanisms can allow, is to use substrate cycles at key points in the metabolic pathway concerned [81]. Such a cycle in mitochondria would have the effect of making the mitochondria ‘inefficient’, ie causing it to oxidise substrate to H2O and CO2 without generating maximal energy. Uncoupling proteins allow precisely this to happen: other mechanisms can also be imagined to achieve this in oxidative phosphorylation.

The physiological benefit of such cycles is that the body can respond rapidly to increased energy demand. The downside is that you need more mitochondria at rest (because each is less efficient), and some resting energy is ‘wasted’, ie dissipated as heat.

The paradoxical effects of RAS and the SNS can therefore be seen as the cell’s response to chronic stimulation from hormonal systems that alert the body to the need for immediate, substantial energy demand, through increasing mitochondrial number and mitochondrial responsiveness. Blockade of these systems signals a reduction in stress demand and hence the need for fewer, more efficient and less potentially responsive mitochondria. This relates to muscle mass because mitochondrial cycling is not something that can be switched on and off on a matter of minutes – protein synthesis, and creation of new mitochondria take hours or days. If a patient has their RAS chronically blocked, genetically or pharmacologically, then the number of mitochondria will fall and their ability to rapidly increase energy output will fall. When such muscle is exercised, it will rapidly reach its limit of oxidative phosphorylation and move into a glycolytic metabolism, typical of sprint rather than marathon training regimes. This will result in more muscle build-up, as it does in more conventional training. For patients suffering severe muscle wasting (cachexia), even everyday tasks would become sprint training tasks, resulting in muscle build-up (or slowing of muscle decline).
Hypothesis: chronic lack of ras/sns stimulation maintains CFS

My hypotheses is that the failure of CFS patients to maintain power output in physical or mental activities is due to an inability of their metabolism to deliver increased energy in response to increased demand. This is a key component of the maintenance of CFS. Any event that causes the patient to reduce their exertion to a low level might trigger the state: the likelihood that it did so would be influenced by other physiological and genetic factors. Once the capacity to increase energy production on demand has been reduced, any exercise will be ‘felt’ to be like heavy exertion, and will rapidly cause the muscle to become hypoxic, generating lactic acid, and sometimes causing muscle damage more normally associated with over-exercise. Depending on other physiological and psychological factors, this may be sufficient to deter the individual from exercising, maintaining a vicious cycle. This is illustrated in Figure 1.

This means that treating the initial, triggering causes of CFS – viral infection, injury, inflammation, depression – are very unlikely to be cure the disease: this is found to be the case. The only two approaches likely to be effective are

i. increasing physical activity: this is the only therapeutic approach presently shown to have an effect

ii. increasing mitochondrial mass and responsiveness

I propose to treat CFS through the second of the two options above. The pharmacology for doing this could include use of stimulants of the renin-angiotensin system, or sympatheticomimetic agents, especially beta adrenergic agonists such as salbutamol, thiotropium or ephedrine. In practice, because of the redundancy of biological circuitry and the need to avoid unwanted pharmacological effects, combinations of low doses of these compounds are likely to be the best approach.

I note that this is unlikely to be a ‘universal cure’. In some groups of patients other factors than cell-level power generation may be a dominant maintaining factor, and in particular in some defects in neuromuscular transmission or inappropriate psychological attitudes are strongly suspected to be important in the disease [59]. However it is plausible to suggest that this approach will be of some use to a lot, maybe a majority of patients, and as it is very easy to administer and should have a rapid effect, if proven successful it could be used as a ‘first line’ treatment, with more costly and time-consuming psychological and exercise approaches being brought in subsequently.
http://en.wikipedia.org/wiki/Renin-angiotensin_system

edit -

Also: http://www.ncbi.nlm.nih.gov/pubmed/19211721 (vaguely relevant)