Re: exercise harm in ME/enterovirus in muscle - a review;

December 7, 2006

Hi All,

Thanks to everyone in this thread who answered my call for help on

this issue. I can't claim credit for the result, but I did pass on

the references people here supplied, and below is the result. The

principle author is interested in talking to Rich VK btw, if he's

watching!

It pretty much speaks for itself, but it is perhaps highlighting one

aspect from the get-go: competion for Glutatione between muscles and

the immune system. Over-exertion leads to muscles using up

glutathione (depleted in those with ME); the immune system becomes

less able to deal with infection as a result; any " dormant " viruses

then get let loose. So exercise can worsen symptoms and harm people.

I hope this is useful to people here.

Phil

------------------------------------------------------------

The physiology of exercise intolerance in patients with myalgic

encephalomyelitis (ME) and the utility of graded exercise therapy.

ABSTRACT:

This review discusses the suitability of graded exercise therapy for

the treatment of myalgic encephalomyelitis (ME), based on current

knowledge of the underlying physiology of the condition and the

physiological effects of exertion on ME patients. A large body of

peer-reviewed scientific literature supports the hypothesis that

with ME an initial over-exertion (a period of metabolic stress) in

conjunction with viral infection depletes concentrations of the

metabolic regulator glutathione, initiating a cascade of

physiological dysfunction. The immune system and muscle metabolism

(including the muscles of the cardiovascular system) continually

compete for glutathione, inducing a state of constant stress that

renders the condition chronic. The impairment of a range of

functions means that subtly different suites of symptoms are

apparent for different patients. Graded exercise therapy has proven

useful for a minority of these, and the exacerbation of symptoms for

the majority is not subjective but has a physiological basis.

Blanket recommendation of graded exercise therapy is not prudent for

such a heterogeneous group of patients, most of which are likely to

respond negatively to physical activity.

Following exercise, patients with myalgic encephalomyelitis (ME)

uniquely exhibit exacerbated symptoms and a suite of measurable

physiological changes indicative of stress (sub-optimal metabolic

performance; e.g. reduced respiration and heart rate, increased

glycolysis and lactic acid production, and concomitant limitation of

activity1-5). Although these symptoms may not be universal6, a

significant subgroup of ME patients are affected in this manner7.

The issue of exercise is critical for the treatment of the condition

as one school of thought recommends " graded exercise therapy " as a

general remedy for ME whilst another recognises that exercise

intolerance may have an underlying physiological cause that may

actually be aggravated by physical exertion. This difference of

opinion influences policy: graded exercise therapy is one of the

principal recommendations of the current NICE draft guidelines for

the treatment of patients " mildly to moderately affected " by ME (p.

21, lines 20 to 23) 8. Although recent general reviews of ME exist9-

11, our aim is to specifically review evidence for the mechanisms by

which physical activity affects ME patients, and to investigate how

graded exercise therapy may help or hinder recovery.

Although no single randomised controlled study has yet attempted to

investigate every aspect of ME, the combined weight of empirical

evidence to date indicates that the condition is characterised by a

complex series of events involving reserves of metabolic regulators

such as glutathione, muscle metabolism and the cardiovascular

system. A significant body of literature suggests that these

imbalances are associated with a dysfunctional immune system

impaired by viral infection. Indeed, a hallmark of ME is a range of

symptoms, varying in extent between patients, suggesting that a

range of functions are impaired to greater or lesser degrees.

ME typically follows a flu-like illness, with elevated

concentrations of viral particles subsequently detectable in blood

and muscle tissues12. Post-viral fatigue is a well established

possible consequence of infection by a range of different viruses13-

17, with enteroviruses specifically implicated in the case of ME –

elevated concentrations of viral RNA sequences resembling coxsackie

virus B are detectable in muscle tissue12. Furthermore, the majority

of the limited number of ME patients so far treated with antiviral

drugs (interferons) were able to return to work following

treatment18, also suggestive of a persistent `smoldering

infection'19.

Crucially, post-viral fatigue is not related to the muscle disuse

and deconditioning that can result from the initial period of

illness12. Indeed, the mechanism underpinning post-viral fatigue is

a multifaceted physiological imbalance. Nijs and co-workers20 found

that, for ME patients, graded exercise resulted in faulty regulation

of the immune system, specifically increased activity of the

enzymes " elastase " and " RNase L " . RNase L is a key component in the

cell's virus detection system and is up-regulated in response to

viral infection. However, elastase degrades RNase L and is normally

involved in removing it from the cell when concentrations are too

high. Why should both be highly expressed in ME patients? Elastase

is activated and degrades the RNase L in the absence of metabolic

regulators such as glutathione. (Glutathione is an amino acid

complex that modifies enzyme activity throughout the body, and ME

patients exhibit either lower concentrations or an imbalance between

its active and inactive forms21-23.) Thus the simultaneous over-

activation and mis-regulation of this part of the immune system can

be explained by glutathione depletion. A range of factors contribute

to glutathione depletion in the general population, including

infection, the oxidative stress induced by strenuous or sustained

exercise, and the long-

term elevation of the stress hormones cortisol and adrenalin24.

Furthermore, glutathione is also involved in sustaining respiration

(i.e. the production of chemical energy compounds such as ATP in the

mitochondria) thereby providing energy for active tissues such as

muscle. Thus muscle tissue effectively competes with the immune

system for glutathione25 – sustained physical activity reduces the

amount of glutathione available to the immune system, resulting in

immune dysfunction. Conversely, an overactive immune system reduces

the amount of energy available for muscle tissue, also exacerbating

oxidative stress, and can account for both the chronic fatigue and

pain (by inducing lactic acid production) that characterise ME.

Thus, following an initial period of stress, glutathione

concentrations may be too low for the optimal function of both the

immune system and muscle tissues, paving the way for both persistent

viral infection and fatigue, both of which feedback from each other

to render the condition chronic.

This situation is compounded by the fact that glutathione not only

has a supporting role in the immune response but also directly

inhibits the replication of enteroviruses by blocking the formation

of one particular protein (glycoprotein shared by all – including

coxsackie viruses. Indeed, glutathione concentration is a major

factor influencing the expression of other persistent viral

infections such as HIV26-29. Thus glutathione depletion not only

suppresses the immune system, it leaves the body particularly

defenceless against enteroviruses. Sustained exercise or stress can

deplete glutathione concentrations to the point where viral RNA is

no longer prevented from replicating, aiding either an initial

infection or the renewed replication of previously blocked viral RNA

present in muscle tissue and blood27,29. Thus glutathione depletion

is a strong candidate for `the trigger for reactivation of

endogenous latent viruses' in ME30. A small number of studies

demonstrate that foods rich in glutathione or direct glutathione

injection help to relieve fatigue in ME patients, and may clear

active viral infections31,32.

Although the above studies have concentrated on skeletal muscle, the

heart (and the postural leg muscle involved in pumping blood back to

the heart) is not exempt from glutathione depletion. Thus the above

mechanism can also account for the range of cardiovascular problems

associated with ME, including orthostatic (standing) intolerance

(reviewed by Spence and 33). Patients with orthostatic

intolerance `have continuous disability and commonly have exercise

intolerance'33.

Together, this evidence suggests that chronic fatigue in ME is

symptomatic of the following sequence of events: a period of

infection or strenuous physical or mental activity results in

glutathione depletion; this renders the immune system relatively

ineffective, particularly against enterovirus infection; the immune

system becomes constantly activated (and inefficiently governed)

because it has insufficient resources (glutathione) to completely

rid the body of viral particles; the constantly elevated energy

demand of the immune system detracts from other metabolic functions

(particularly energy-demanding systems such as skeletal muscles and

the cardiovascular system); limitation of respiratory and

cardiovascular systems further locks the patient into a vicious

cycle of inefficient energy production and use; increased reliance

on anaerobic metabolism leads to lactic acid production and

associated muscle pain.

Clearly, the performance of energy-demanding activities such as

exercise can only aggravate this situation. Indeed, 82 % of ME

patients in a recent study stated that graded exercise therapy

worsened their condition, and only 5 % found it useful (compared to

70 – 75 % of patients who found either pain management or `pacing'

of daily activities useful)34. Furthermore, the Canadian Clinical

Treatment Protocol warns that " externally paced `Graded Exercise

Programs' or programs based on the premise that patients are

misperceiving their activity limits or illness must be avoided " 35.

If exercise is so detrimental, why is graded exercise therapy often

recommended as a treatment for ME? Firstly, many of the studies

cited here are recent, and the information and implications have

perhaps not yet filtered up to policy makers. Secondly, the

reclassification of ME as an ambiguous `chronic fatigue syndrome'

(CFS) by members of the psychiatric profession assumes that the

symptoms have no physiological basis and are best treated with the

traditional psychiatric method of facing and overcoming a problem,

rather than direct removal of the problem at source. However, this

approach jumps from hypothesis to treatment without investigating

the mechanisms involved, perhaps explaining why " no psychiatrist has

ever cured an M.E. patient using psychiatric treatments " 19.

Psychiatry, by definition, should not have authority over the

treatment of physiological disorders, particularly those that occur

chiefly in muscle tissues. Graded exercise therapy is founded on,

and perpetuates, the myth that ME patients are simply malingering,

while most are frustrated by their incapacity to satisfactorily

conduct critical aspects of daily life34.

ME is a heterogeneous disorder that affects different patients to

varying degrees and with subtly different suites of symptoms. At

best, graded exercise therapy has relieved symptoms for (but not

cured) a tiny minority of patients, whilst the weight of empirical

evidence indicates that exercise has direct and persistently

negative impacts on the physiology and quality of life of a

significant subgroup of ME patients. Any universally applied therapy

is unlikely to address the heterogeneity of ME, and graded exercise

is particularly unsuitable as it may worsen the condition, and

should not be generally recommended without a high degree of

confidence that it will not be applied to susceptible patients: it

is difficult to conceive of a more inappropriate therapy for ME. By

increasing the risk of relapse and overall health risks, rather than

reducing them, graded exercise therapy also risks increasing the

burden of illness on society at large. The present review suggests

that an approach based on treatment of the underlying physiological

dysfunction will be more fruitful.

Abbreviations

ATP = Adenosine triphosphate, RNase L = 2',5'-oligoadenylate (2-5A)

synthetase/Ribonuclease L

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8 National Institute for Health and Clinical Excellence (NICE).

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13 Ayres JG, Flint N, EG, et al. 1998. Post-infection fatigue

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E & De Meirleir K. 2005. Chronic fatigue syndrome: exercise

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Free radicals in chronic fatigue syndrome: cause or effect? Redox

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22 y Keenoy B, Moorkens G, Vertommen J, Noe M & De Leeuw I.

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25 Bounous G & Molson J. 1999. Competition for glutathione

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1991. N-acetycysteine inhibits latent HIV expression in chronically

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Deresinski SC, Ross W, Sussman H, Raju PA, MT, W, Ela

SW, Herzenberg LA & Herzenberg LA. 1992. Intracellular glutathione

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Garaci E & Rotilio G. 1997. Loss of GSH, oxidative stress, and

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Biology & Medicine 34(7): 928-936.

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part of the pathogenesis of chronic fatigue syndrome? Presented at

the AACFS Seventh International Conference, Oct. 8-10/2004, Madison,

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injections. CFIDS Chronicle January/February 1998.

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December 7, 2006

Thanks for this; is this published (or going to be), and where? And who are the

authors?

>

> Hi All,

>

> Thanks to everyone in this thread who answered my call for help on

> this issue. I can't claim credit for the result, but I did pass on

> the references people here supplied, and below is the result. The

> principle author is interested in talking to Rich VK btw, if he's

> watching!

>

> It pretty much speaks for itself, but it is perhaps highlighting one

> aspect from the get-go: competion for Glutatione between muscles and

> the immune system. Over-exertion leads to muscles using up

> glutathione (depleted in those with ME); the immune system becomes

> less able to deal with infection as a result; any " dormant " viruses

> then get let loose. So exercise can worsen symptoms and harm people.

>

> I hope this is useful to people here.

>

> Phil

>

> ------------------------------------------------------------

>

> The physiology of exercise intolerance in patients with myalgic

> encephalomyelitis (ME) and the utility of graded exercise therapy.

>

> ABSTRACT...

December 7, 2006

Hi, Phil.

It is very gratifying to see that somebody is taking seriously some of

the things I've been writing. I would be very pleased to talk to the

principal author of this piece. My email address is richvank at aol

dot com.

Rich

>

> Hi All,

The

> principle author is interested in talking to Rich VK btw, if he's

> watching!

December 7, 2006

Quote from article:

" Many CFS patients relate the onset of their symptoms to a preceding

viral infection from which they believe they failed to recover

fully. Evidence supporting such attribution had been largely

anecdotal until recent prospective studies found evidence of

protracted fatigue states following certain laboratory confirmed

infections, supporting the concept of a postviral or postinfectious

fatigue syndrome.4–7,11

We reported previously that a subset of CFS patients had abnormal

lactate responses to exercise at work rates below the predicted

anaerobic threshold.19 Such cases proved less likely to have

evidence of psychiatric disorder than cases with normal lactate

responses, and the finding could not be explained satisfactorily by

the effects of deconditioning or muscle disuse, either on the basis

of heart rate responses to exercise19 or from a subsequent analysis

of muscle fibre sizes and fibre type proportions.20 Further studies

using phosphorus magnetic resonance spectroscopy have shown that

some CFS patients have defective muscle energy metabolism,21–23

notably reduced ATP resynthesis rates following exercise, suggestive

of mitochondrial dysfunction.21 "

Wow. No " stress or stressors " " personality types " " diet " " exercise "

or " lack of exercise " involved.

A virus! Doesn't much care about your individual quirks.

What a concept!

-

December 7, 2006

That fits me to a tee...but then, I can't believe that stress is

still an issue and we still have to hear people psychologize this

illness.

Would you please, let me know, whether Mold Warriors contains the

info that Desperation Medicine has, or does one have to buy both?

Also, is mold avoidance the main way you deal with mycotoxins? I

think that Cholestyramine would not be good for me...am thinking

Chronic Bowel Obstruction.

TIA,

Amelia

>

> Quote from article:

> " Many CFS patients relate the onset of their symptoms to a

preceding

> viral infection from which they believe they failed to recover

> fully. Evidence supporting such attribution had been largely

> anecdotal until recent prospective studies found evidence of

> protracted fatigue states following certain laboratory confirmed

> infections, supporting the concept of a postviral or postinfectious

> fatigue syndrome.4–7,11

>

> We reported previously that a subset of CFS patients had abnormal

> lactate responses to exercise at work rates below the predicted

> anaerobic threshold.19 Such cases proved less likely to have

> evidence of psychiatric disorder than cases with normal lactate

> responses, and the finding could not be explained satisfactorily by

> the effects of deconditioning or muscle disuse, either on the basis

> of heart rate responses to exercise19 or from a subsequent analysis

> of muscle fibre sizes and fibre type proportions.20 Further studies

> using phosphorus magnetic resonance spectroscopy have shown that

> some CFS patients have defective muscle energy metabolism,21–23

> notably reduced ATP resynthesis rates following exercise,

suggestive

> of mitochondrial dysfunction.21 "

>

> Wow. No " stress or stressors " " personality

types " " diet " " exercise "

> or " lack of exercise " involved.

> A virus! Doesn't much care about your individual quirks.

> What a concept!

> -

>

December 8, 2006

" lifelonglearner79 " wrote:

> That fits me to a tee...but then, I can't believe that stress is

> still an issue and we still have to hear people psychologize this

> illness.

>

> Would you please, let me know, whether Mold Warriors contains the

> info that Desperation Medicine has, or does one have to buy both?

> Also, is mold avoidance the main way you deal with mycotoxins? I

> think that Cholestyramine would not be good for me...am thinking

> Chronic Bowel Obstruction.

> Amelia

I hear ya' on that!

In 2001 I moved into a place that put me " below the power curve " of

long term exposure - more than I could endure.

Wasn't all that ferocious, not like walking into a sick building,

but this adds up over time, and I could tell that I was

gradually " slipping " and heading in a very bad direction.

CSM only scrubs toxins after they've passed through and done their

damage. It's like cleaning up after the Hurricane, doesn't really

protect you in the midst of the storm.

For people " on the edge " , it helps a lot by keeping the mess a bit

better under control, but as long as the mess keeps piling up,

eventually you're gonna get buried.

I did try the CSM at that time, and it did seem to help, just a

bit, but my digestive tract came to a screaming halt.

I finally decided that I had " had enough of this s--t " and just

concentrated on total avoidance - and that's all I do.

And when I look back at all the things that people are trying, and

get a sense of what their results are, it makes me feel fortunate

that I chose to follow this path. Very difficult, complex, life

turned totally upside down - but beats the crap out of the

alternative.

-

December 9, 2006

One of the most useful papers I have read. Where was it published?

Thanks Phil

Phil <fi11ip@...> wrote: