If you visit your local health food store, you'll find shelves loaded with "all-natural" compounds bearing exotic sounding names like "L-carnitine" and "coenzyme Q10." Lately, everyone is buzzing about these and other metabolic supplements with names previously known only to biochemists and doctors. The "Ask the Experts" column on the MDA Web site (www.mda.org) has received questions about the potential benefits of carnitine and coQ10 for almost every disorder covered by the Association. Everyone seems to have heard of carnitine and coenzyme Q10, but what do these compounds normally do in the body? Are they really beneficial in the treatment of neuromuscular disorders and, if so, which ones?

L-carnitine (carnitine) and coenzyme Q10 (coQ10) are natural substances found in all the cells of our bodies that play important roles in energy production. Carnitine and coQ10 both work in the mitochondria -- tiny cucumber-shaped components of cells that can be thought of as the cell's "power plants." The mitochondria are dedicated to transforming the food that we eat into ATP, a form of energy that can be used by our cells (see illustration). Sometimes, when things go wrong with this energy transformation process, supplementing the diet with extra carnitine or coQ10 can have a dramatic, almost magical, effect.

Salvatore DiMauro, an MDA-grantee and expert on mitochondrial disorders at Columbia University in New York, recalls the case about a year ago of a young girl who was brought to New York from Poland for treatment of a life-threatening heart condition.

"Fortunately," DiMauro says, "someone was smart enough to send my lab a tube of blood. We measured her carnitine levels and they were extremely low. The diagnosis of primary carnitine deficiency was easy. This girl was put on high doses of carnitine and, three weeks later, her heart, which was huge, had shrunk back to normal. Now she's a ballet dancer. It's incredible this complete recovery."

DiMauro adds that treating primary deficiencies in carnitine or coQ10, in which there is an abnormally low amount of these compounds in the body, is rewarding for people working in a field that isn't used to great therapeutic successes.

But what about the far more common conditions for which carnitine and coQ10 are being sold over the counter? Advertisers and some researchers claim that these substances can increase muscle strength (of interest to anyone with muscle weakness), treat any number of heart conditions (common problems with neuromuscular disorders), increase overall energy levels (a universal goal in neuromuscular disorders), and add to the body's ability to fight free radicals (of special interest to those with amyotrophic lateral sclerosis, or ALS).

"There is a lot of sex appeal in these metabolic substances," says George Karpati, an MDA grantee and neurologist at the Montreal Neurological Institute who, in 1975, first successfully used carnitine to treat a young patient with muscular weakness and liver and brain dysfunction. Karpati has also conducted studies on the effects of coQ10 on some mitochondrial disorders. "They're natural substances and you can draw pretty diagrams where you can indicate that they do a lot of good in the body, but that doesn't change the bottom line."

So, word-of-mouth and unsubstantiated advertising aside, what is the bottom line? How many of the claims for carnitine and coQ10 are scientifically justified, and for which neuromuscular disorders might they be beneficial? Just because these compounds are "natural" and involved in certain essential bodily functions doesn't mean that taking more of the substance will increase its normal activities in a beneficial way. For instance, sometimes the body is only capable of absorbing so much of a substance and no more -- in this case, by taking supplements, you'll only produce, as one doctor put it, "expensive urine."

On the other hand, under certain circumstances, such as the case of DiMauro's patient, supplements can be life savers. Carnitine and coQ10 fall into an odd category of unregulated medications -- because they're normally produced in the body, they're considered supplements (like vitamins) and can be sold over the counter. At the same time, both of these supplements have dramatic medical applications, and should be taken by some people. Outside of these documented situations, the evidence for their beneficial effects is less clear. The good news is that neither carnitine nor coQ10 has any known serious side effects.

CARNITINE IS IN THE ESCORT BUSINESS

Carnitine is a small molecule that works in the "shipping and receiving department" of the mitochondrion, where traffic going in and out of the matrix (inner compartment of the mitochondrion) is sorted (see illustration). At shipping and receiving, security is tight -- not just any molecule is allowed through the inner membrane. In fact, large long-chain fatty acids can't make it through the membrane at all without carnitine to escort them.

Getting long-chain fatty acids into the mitochondrial matrix turns out to be important because fatty acids are a major source of energy for your heart and skeletal muscle. During rest, about 70 percent of the energy requirements of skeletal muscle are met by burning fatty acids and, during sustained exercise, after glucose (sugar) supplies have been exhausted, the primary fuel source again becomes fatty acids.

In addition to escorting fatty acids into the inner compartment of the mitochondrion, carnitine also moonlights as part of the hazardous materials cleanup crew. By binding to extra metabolic products that aren't being used by the cells, carnitine is able to escort them out of the muscle and, ultimately, out of the body in the urine. Normally, only carnitine that is bound to other molecules is lost in the urine.

Although most of the body's carnitine can be found in the voluntary and cardiac muscles, the muscle cells themselves can't make carnitine. About 75 percent of the body's carnitine requirement is derived from the diet (red meat, poultry, fish and dairy products) and the rest is made in the liver and kidneys. Free carnitine in the blood is actively imported into muscle cells through a specific carnitine transporter.

WHEN CARNITINE HELPS

See larger illustration

Both DiMauro and Karpati agree that, when the amount of carnitine in the body is unnaturally low, as in primary carnitine deficiency, carnitine supplementation can be a very effective treatment.

A shortage of carnitine causes a variety of problems in the body. First, because carnitine is required to move long-chain fatty acids into the mitochondrial matrix for further processing, an inadequate supply of carnitine means that the body can't use this important fuel source for energy. The decrease in available energy results in muscle weakness, particularly after sustained activity or during fasting.

A second problem is that unused metabolic products, including fatty-acid compounds, begin to build up in cells. According to DiMauro, this abnormal buildup of fatty-acid compounds can act like a "detergent" to dissolve portions of the cell membrane. A build-up of fatty acids can also wreak havoc on other aspects of metabolism.

WHAT CAUSES CARNITINE DEFICIENCY?

Carnitine deficiency can be caused by genetic defects or environmental factors such as diet and medication. The inherited carnitine deficiencies, disorders covered by MDA, are broken down into "primary" and "secondary" carnitine deficiency.

If you're one of the rare people who has a primary carnitine deficiency, you have a severe shortage of carnitine (less than 10 percent of normal) in the blood or in specific tissues. A recent study has confirmed that low tissue levels of carnitine are caused by a faulty carnitine transporter that prevents this vital molecule from getting into the proper cells. A faulty transporter can also cause low levels of carnitine in the blood by allowing free carnitine to be excreted in the urine instead of being reabsorbed by the kidney. Primary carnitine deficiency is classified as "systemic carnitine deficiency," which involves many organs including the heart and brain, or "muscle carnitine deficiency," which is restricted to voluntary muscle.

The symptoms of primary carnitine deficiencies, which can include everything from muscle weakness to heart and brain dysfunction, respond well to carnitine supplementation. The idea is that even though the carnitine transporter is defective, by flooding the system with high concentrations of carnitine, enough will get into the cells where it's needed.

If you have a mitochondrial disorder, you may also be at risk for a carnitine deficiency. Carnitine deficiency can occur as a secondary effect from a variety of mitochondrial disorders, in particular those involving the preliminary processing of fatty acids, such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, and those affecting the electron transport chain, such as cytochrome c oxidase deficiency.

When some element of the mitochondrial assembly line is defective, "raw" metabolic products begin to back up (picture the famous candy factory episode of "I Love Lucy"). Carnitine becomes bound to the extra metabolites and delivers them to the kidney, where both compounds are excreted in the urine. The net result of this activity is that the overall amount of carnitine in the body can become reduced because the kidneys excrete so much of the bound form. Carnitine supplements are sometimes given to people with mitochondrial disorders to try to improve the ratio of free to bound carnitine. This therapy, as in primary carnitine deficiency, has met with varying degrees of success.

Carnitine deficiency has also been documented occasionally in people with Duchenne muscular dystrophy, probably as a result of "leaky" muscle membranes, DiMauro says. Because carnitine is such a large component of muscle, he explains, supplementation is certainly not going to do any harm. However, he's quick to caution that people shouldn't think that carnitine is a therapy for muscular dystrophy.

Finally, environmental factors can also cause carnitine deficiency. Certain medications, such as the anti-seizure drug valproic acid (Depakene), or special diets, such as strict vegetarianism, can lead to carnitine deficiencies. In these cases, carnitine supplementation can help counteract these factors. Your doctor can give you more information about when you might be at risk for carnitine deficiency.

If you have a neuromuscular disorder and aren't sure if you should be taking carnitine, check with your doctor. When you have your blood carnitine levels checked, you'll want a measurement of both total and free carnitine so that the amount of carnitine that is bound to other metabolites can be calculated. Even if your total carnitine levels are normal, when too much carnitine exists in the bound form, a frequent problem with many mitochondrial disorders, muscle weakness can occur.

WHEN CARNITINE DOESN'T HELP

Both DiMauro and Karpati stress that supplemental carnitine is probably only beneficial to someone whose carnitine levels are decreased due to primary or secondary carnitine deficiencies, or in cases when medication or diets result in carnitine deficiency.

"Any other situation when carnitine is used -- for general tiredness, fatigue, improved athletic performance or ailments in which carnitine levels aren't low -- is out of desperation," Karpati says. "There is no evidence whatsoever that, under those circumstances, carnitine supplementation is justified and useful."

In fact, there is evidence that the system that absorbs carnitine from the intestine into the body may be "saturable." This means that the body can only absorb so much carnitine at one time, no matter how much you take in. Also, although most free carnitine will be retained by the kidneys when circulating carnitine levels are normal, if the amount of free carnitine in the blood is above normal, the kidneys will excrete it -- producing "expensive urine."

Carnitine is available as an FDA-approved prescription drug called Carnitor, made by Sigma Tau Pharmaceuticals. Carnitine is also sold over the counter at health food stores, drug stores and on the Internet. The product sold over the counter as "L-carnitine" theoretically contains the same chemical compound as the prescription brand Carnitor; however, both DiMauro and Karpati admit to being biased toward the prescription brand because products sold as supplements aren't subject to strict regulatory control. According to one study at Duke University Medical Center many nonprescription brands of carnitine didn't dissolve properly. Another consideration is that the prescription form may be covered by health insurance.

Carnitor costs about $3.10 per gram for the liquid form and $2.70 per gram for tablets. The average price of carnitine sold over the counter varies from 75 cents per gram to $2.50 per gram. The therapeutic dose for adults with carnitine deficiencies is 1 to 3 grams per day. The dosage for children is about 40 to 100 milligrams per kilogram of body weight. If you have a neuromuscular disorder, consult with your doctor before taking any nutritional supplement.

There are almost no side effects from carnitine, DiMauro says, other than the occasional instance of diarrhea in children, which can be taken care of by adjusting the dosage.

CoQ10 -- WORKING ON THE CHAIN GANG

CoQ10, also known as ubiquinone, is a fat-soluble molecule made in all cells. Remember that carnitine works in the shipping and receiving department of the mitochondrial factory. CoQ10 works on the main factory floor as a member of the assembly line that extracts energy from the raw materials sent into the mitochondrion. This assembly line, in the inner mitochondrial membrane, is called the electron transport, or respiratory, chain.

Another role of coQ10 is its ability to act as an antioxidant. Although most of the oxygen used by the electron transport chain ends up as part of neutral water molecules, sometimes oxygen molecules lose an electron and become "charged." In large quantities, these charged oxygen molecules, known as oxygen free radicals, can be very destructive to the membranes of the cell.

The cellular damage that occurs in many mitochondrial abnormalities and some neurodegenerative diseases, such as ALS, is thought to be linked to or worsened by excess free radical production -- known as "oxidative stress."

Research has shown that coQ10 is able to participate in a cellular buffering system designed to protect against oxidative stress. Scientists think that coQ10 acts as an "antioxidant" in the cell because it has the ability to neutralize the charged oxygen molecules without becoming destabilized itself, thus stopping the destructive chain reaction. CoQ10 might also juggle electrons back and forth with vitamin E to help neutralize excess charges.

WHEN CoQ10 WORKS

This little, unassuming molecule that works in our mitochondria has been hailed by the health food industry as the "fountain of youth." Claims have been made that coQ10 can prevent heart disease, cancer, neurodegenerative diseases and old age.

So what is the evidence that coQ10 supplementation is really medically beneficial? Unfortunately, the therapeutic benefits of coQ10 for most situations remain unresolved because of a lack of well-controlled studies.

Karpati says, "Whenever you evaluate any of these agents, you have to use objective endpoints to determine their usefulness. Subjective endpoints such as 'I feel better,' 'I can do more' or 'I'm more upbeat' aren't sufficient."

As with carnitine, the only noncontroversial dramatic benefits of coQ10 supplementation have been seen in those people who, owing to a genetic defect, have decreased levels of coQ10 in their cells, a condition known as primary coQ10 deficiency.

"We've seen an increasing number of patients with very low levels of coQ10 in the muscle," DiMauro says. He also describes a type of coQ10 deficiency that is manifested in the nervous system and results in a decrease in muscle coordination (ataxia). Both of these primary coQ10 deficiencies respond very well to treatment with this supplement, DiMauro says.

WHEN coQ10 MIGHT BE WORTH A TRY

People with disorders affecting the mitochondria will recognize coQ10 as a common element of the "metabolic cocktail" -- a variable group of vitamins and supplements frequently taken for mitochondrial diseases; however, there is no evidence that coQ10 is lower than normal in most of these diseases.

"So what is the rationale?" DiMauro says. "It could be one of trying to increase the amount of coQ10 to favor electron flow. It's more likely that coQ10 is given because of its antioxidant properties."

DiMauro explains that because the electron transport chain is the main source of oxygen free radicals, a malfunction in this chain (as occurs in some mitochondrial disorders) can result in an even larger accumulation of free radicals, so coQ10 is given to try to offset this accumulation.

But does coQ10 supplementation really help in mitochondrial disorders? The few published studies produced mixed results. More recent studies have concluded that there are benefits to coQ10 supplementation.

You may have heard that coQ10 could be useful in the treatment of heart conditions that can occur in conjunction with many neuromuscular disorders, including, but not limited to, muscular dystrophy, mitochondrial myopathies and myotonic dystrophy (MMD). Although many studies of coQ10 in the treatment of various types of heart conditions have been carried out, again, the results have been mixed. If coQ10 provides any benefit in these conditions, it's probably a slight benefit.

Finally, the ability of coQ10 to act as an antioxidant has also led researchers to the substance in the treatment of neurodegenerative diseases thought to be linked to oxidative stress. MDA-funded researcher M. Flint Beal of Cornell University in New York, has conducted experiments to determine whether coQ10 can protect motor neurons from the cell death that normally occurs in ALS.

In a controlled study published in the July 1998 issue of the Proceedings of the National Academy of Sciences, Beal found that mice with ALS taking coQ10 survived significantly longer than mice with ALS that weren't given the supplement. Although these results seem promising, more experiments will be required.

The good news is that coQ10 has no known side effects, and it's available over the counter at health food stores and pharmacies. The 30-milligram size, the daily dosage suggested by many health food suppliers, sells for about 33 cents a tablet. Be aware that concentration and purity can vary, and remember to consult with your doctor before taking any supplement on a regular basis. CoQ10 isn't currently available in a prescription form.