THE CORE OF THE PROBLEM: TOO MUCH CALCIUM IN THE MUSCLE CELL

When central core disease was first described in 1959, almost nothing was known about the molecular problems that cause the disease. Now, 40 years later, we're getting a handle on the causes of this elusive neuromuscular disorder.

New research from MDA grantee David MacLennan of the University of Toronto and collaborator Tommie McCarthy of the University of Cork, Ireland, suggests that too much calcium in the wrong part of the muscle cell could be the problem.

1. NORMAL MUSCLE CONTRACTION When the nervous system signals the muscle cell to contract, an electrical signal is sent from the surface of the muscle cell to the inner part of the cell through the T-tubule.		2. A CLOSER VIEW OF THE T-TUBULE AND SARCOPLASMIC RETICULUM The electrical signal traveling through the T-tubule activates the ryaodine receptor to release calcium from the sarcoplasmic reticulum. The calcium washes over the actin and myosin filaments and makes them squeeze together. Calcium is then pumped back into the sarcoplasmic reticulum through a special pump.

We all know that calcium is required for strong bones, but you might not know that calcium also plays an important role in all of our cells. Muscle cells respond to messages from the brain with a burst of calcium. This increase in calcium in the main part of the muscle cell allows filaments in the cell to slide past one another and make the cell shorter. When thousands of muscle cells become shorter, the end result is muscle contraction.

Exposure to too much calcium for too long is actually harmful to a muscle cell. High calcium levels are especially damaging to the mitochondria, the cells' "power plants." The muscle cell gets around this problem by storing high concentrations of calcium in a special compartment, the sarcoplasmic reticulum, which is separate from the rest of the cell.

When the nervous system signals the muscle cell to contract, a short burst of calcium is allowed to flood out of the sarcoplasmic reticulum through a special "pore" called the ryanodine receptor. The calcium stays in the main part of the cell just long enough to start the contraction process, and is then pumped back into the sarcoplasmic reticulum by a calcium pump.

Researchers have found that many people with CCD have genetic mutations in the DNA that codes for the ryanodine receptor. MacLennan wondered if the mutations in this receptor might affect the way calcium is contained in the sarcoplasmic reticulum.

To study this question, he cloned the faulty ryanodine receptor gene from members of one large family in which cases of CCD are particularly severe. He then put the DNA for the mutated ryanodine receptor into cells in a culture dish and allowed these "host" cells to manufacture the mutated ryanodine receptor.

MacLennan found that the cells expressing the CCD-causing ryanodine receptor had higher levels of calcium in the main part of the cell than cells without the mutant receptor. Based on this and other observations, MacLennan concluded that the ryanodine receptor from this family with CCD is "leaky" -- that is, calcium is able to leak out of the sarcoplasmic reticulum even when the nervous system isn't signaling the muscle.

MacLennan suspects that the constant leak of calcium from the sarcoplasmic reticulum in the muscle cells of people with CCD may cause two types of problems.

First, because calcium isn't properly contained in the sarcoplasmic reticulum, when the nervous system signals the muscle cell to contract, there's less calcium available to create the calcium "burst" required for contraction. This problem is akin to a telegraph operator who, instead of tapping out a message, holds the button down lightly all the time.

The second problem that can occur is that the constant high levels of calcium may destroy mitochondria in the center of the muscle cell. MacLennan suspects that the remainder of the cell may be able to expel excess calcium, but extra calcium in the center of the cell is taken up by the mitochondria, destroying them.

The metabolically inactive "cores" in the muscle fibers of people with CCD may represent the cell's attempt to "wall off" areas of the cell that aren't able to deal with the extra calcium.

It isn't known which of these two problems might be the primary cause of muscle weakness in CCD. MacLennan is currently funded by MDA to study the proteins involved in calcium regulation in muscle cells, and he intends to compare the calcium-regulating proteins and their activity from people with mild CCD to those from people who do not have CCD or have severe CCD.

MacLennan suspects that the muscle cells of some people may be better at coping with the calcium leak than others. He hopes that learning how some muscle cells are able to deal with extra calcium may pave the way for developing treatments for people with CCD whose muscle cells don't seem to have these coping mechanisms.

NOTE: The problem of the muscle cell's regulation of calcium has nothing to do with the calcium in your diet. You still need dietary calcium for strong bones, and cutting down on your intake of calcium won't have any effect on what goes on in the muscle cells. 

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