Muscle pain, muscle weakness and Malignant Hyperthermia. Is There a Connection?

Surprising revelations concerning the association of MH with Drug induced muscle pain; muscle weakness with age; and an inherited syndrome of muscle weakness.

Those of you who read my blogs or have read recent information about Malignant Hyperthermia know that the basic defect in MH is an abnormal increase in calcium levels in the muscle cell. The most common reason for such an increase is a structural abnormality of a calcium channel within the muscle cell called the ryanodine receptor when the patient is exposed to certain gas anesthetics and the paralyzing agent succinylcholine (for more information view the slide show on the MHAUS web site).  In turn a change in DNA in the gene that is responsible for the elaboration of this channel is often found.  The gene is called RYR-1. There is a RYR-2 and 3, but those genes are responsible for calcium channels in other tissues.   Such DNA changes, called mutations are found in 70% of MH susceptible. You also know that under ordinary circumstances the vast majority of MH susceptible patients display no outward signs of the disorder such as muscle weakness, muscle cramps, or scoliosis.  On the other hand a small number of MH susceptible patients do display muscle breakdown with exercise or exposure to heat. In yet a smaller number of patients, an acute MH event may occur leading to death.  Some of my blogs have discussed these rare situations.  In October 2010 I suggested a classification of presentations of MH in order to distinguish the various presentations of MH as follows:

MH Type one is associated with RYR 1 mutations or mutations in a protein that influences calcium release from the ryanodine receptor (the dihidropyridine receptor, DHPR). These patients develop MH on exposure to the known triggering anesthetics.

MH type two, are patients with RYR-1 mutations or mutations in the dihidropyridine receptor gene (DHPR) who display either signs of outright MH or just muscle breakdown in association with other drugs, or environmental factors.

Then I suggested that there are certain “MH like syndromes”

Type A. Normal RYR-1 /DHPR gene in combination with two or more compounds that lead to increased release of calcium from storage sites in muscle. Such drugs include caffeine, halothane, and certain drugs of abuse such as “Ecstasy”.

 Type B. Normal RYR-1/DHPR and along with increased cell calcium due to decrease in sarcoplasmic reticulum calcium buffering proteins.

Type C. Normal RYR-1 /DHPR in a patient with certain muscle disorders that experience MH signs following exposure to calcium releasing agents.  For example, Duchenne or Becker’s Muscular Dystrophy patients. They do not have mutations in the RYR-1 gene.

In recent months there have been several studies that show that RYR-1 mutations may lead to 1. An abnormal response to a widely used non anesthetic drug. 2. Muscle weakness associated with aging and 3. Yet another muscle disorder.

In the first case, researchers at the Robert Guthrie Molecular Genetics Research Laboratory in Buffalo  NY, under the direction of Dr. Georgirene Vladutiu showed that some patients  taking lipid lowering drugs (statins) who experience muscle pain, breakdown and weakness  harbor mutations in the RYR-1 gene.(1). The most well known statin is Lipitor.  As Dr. Vladutiu describes her studies: “Severe statin myopathy is defined as having incapacitating muscle pain, cramps or weakness that were not present before beginning statin therapy. Patients with these symptoms may have increases in their blood of a muscle protein, creatine kinase (CK), that may be released from muscle into the bloodstream with muscle injury or muscle disease. Most individuals with statin myopathy who have mutation-proven underlying muscle disease have CK levels at least 4 times the upper limit of normal, however, not all patients with severe statin myopathy have CK elevations. Some patients with severe statin myopathy have continued or even progressive symptoms even after stopping statin therapy. Patients with mild statin myopathy usually experience pain or weakness attributed to statin therapy but are not incapacitated by it and usually recover quickly with the cessation of therapy.” Her team at the Guthrie Laboratory thought that some of the patients might have genetic changes associated with a variety of muscle disorders.  They therefore began a search to determine if patients with statin related myopathy have evidence of DNA changes found in several muscle disorders. They tested a total of 885 patients in 4 groups: severe statin myopathy, mild statin myopathy, statin-tolerant controls, and patients with non-drug-induced myopathies of unknown etiology. Among their findings, disease-causing mutations or variants were found in the RYR1 gene in 3 of 197 severe statin myopathy patients, 1 of 163 mild statin myopathy patients, 8 of 392 patients with non-drug-induced myopathy and none were found in 133 statin-tolerant controls. One known MH mutation, R614C, in RYR1 was found in both a severe statin myopathy patient and in a patient in the unknown myopathy group. The other variants found have been associated with MH but are still under investigation to prove their pathogenicity.”(quotes from Dr. Vladutiu). None of those without symptoms displayed mutations.

In their study, they did not look for the presence of many of the other mutations known to be causal for MH for a variety of technical and procedural reasons. That will be done in a future study.  Even though the number is small and the results preliminary, it raises the issue as to whether patients who have severe statin myopathy should be tested for MH susceptibility or at the least treated as if they are MH susceptible.  Considering that millions of people take these medications, even though the incidence of severe myopathy is very low, the total number of patients with this problem may be in the hundreds. Another possible   implication of the findings is that those who are MH susceptible should be carefully monitored for abnormal muscle breakdown when administered statin medications.

The results of the study were unexpected, but not inconsistent with a few scattered reports of positive tests for MH susceptibility from those who experienced adverse effects of stains.

Again, to underline, that these results are preliminary and need to be confirmed by others. I would label this as MH type 2.

In another study, this time in animals, researchers in Dr. Andrew Marks laboratory at the Clyde and Helen Wu Center for Molecular Cardiology at Columbia University, demonstrated that muscle weakness associated with aging in mice results  from calcium leak through the ryanodine receptor(2).  These animals had a normal RYR-1 gene.  They relate the leakiness to calcium to a protein which they name “calstabin1” linked to the ryanodine receptor.   They demonstrate that a separation of calstabin from the channel is associated with increased cellular calcium levels and reduced muscle strength.  The reason this occurs is rather detailed and is best reserved for another time. They also describe a drug which they call a rycal or S107 that when administered to the aging animal restores muscle tone and power along with the reversal of the calcium leak. Pretty amazing! However, these results were demonstrated in mice and need to be confirmed by others. In addition one of the investigators has a proprietary interest in the new drug. Nevertheless the underlying changes are not inconsistent with findings demonstrated by others. I would label this as MH-like syndrome type A (although the signs of MH are not present).

In the third publication, researchers from Japan  demonstrate that patients with  a rare congenital muscle syndrome, characterized by muscle weakness called congenital Neuomuscular Disease with Uniform Type 1 fiber(CNDMU) , demonstrate an unusual genetic change in the RYR-1 gene that leads to a reduction of calcium release through the ryanodine receptor(3).  Since muscle force generation is dependent on calcium release into the muscle cell, reduced calcium release leads to muscle weakness these patients are apparently not susceptible to MH since their muscle does not show an accentuated response to caffeine in the laboratory setting. However, they also show that when there is a different mutation at the same site then there is an increased calcium release associated with MH triggers and susceptibility to MH.

In other words in one case a particular base substitution in the DNA of the RYR-1 gene (a mutation) at a specific locus of the RYR-1 gene leads to the development of a ryanodine receptor protein that is associated with diminished calcium release, while a different base change at the same site can lead to enhanced calcium release and MH susceptibility.  So, small changes in the DNA structure have a profound influence on the function of a protein and an organ.

The reason I have gone into such detail about these studies is to show how the calcium release channel in muscle , i.e. the ryanodine receptor,  can account for  a wide variety of muscle related  disorders other than MH . These effects range from muscle pain, breakdown and weakness following drug ingestion to age related muscle weakness. The situation with muscle disorders is very complex and confusing.  Many unusual inherited muscle disorders are associated with ryanodine receptor mutations which may either reduce intracellular calcium levels or lead to increased cellular calcium and predispose to MH.

The more I learn about the ryanodine receptor and other proteins associated with intracellular calcium release, the more I appreciate the  importance of this channel  in health and disease and recognize how much more there is to learn.   Malignant Hyperthermia, at least certain types, are just one end of the spectrum of a wide variety of pathologic conditions associated with the ryanodine receptor. As I have stated many times, the study of MH is important because it may provide insight into normal and abnormal muscle pathology.

Next month, I will reflect on the thirtieth anniversary of the founding of MHAUS.

As usual, your comments are welcome and even if you have no comments, let me know what you think of these essays. 

References:
1.Vladutiu GD, Isackson PJ, Kaufman K, Harley JB et al. Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. Molecular Genetics and Metabolism, 2011 Sep-Oct;104(1-2):167-73. Epub 2011 Jul 12.
2.Andersson DC, Betzenhauser MJ, Reiken R , Meli AC et al. Ryanodine Receptor Oxidation Causes Intracellular Calcium Leak and Muscle Weakness in Aging. Cell Metabolism 14,196-7, 2011-09-22
3.Haraki T, Yasuda T, Mukaida K, Migita T et al. Mutated p.4894 RYR1  Function Related to Malignant Hyperthermia and Congenital Neuromuscular Disease with Uniform Type 1 Fiber (CNMDU1). Anesthes. Analgesia 2011, in press