Featured in this article: Charcot-Marie-Tooth disease * Duchenne and Becker MD * Hypokalemic periodic paralysis * Limb-girdle muscular dystrophy * Myoshi myopathy * Myotonic dystrophy * Oculopharyngeal muscular dystrophy * Spinal muscular atrophy
A previously unknown type of muscle stem cell located in the spaces between muscle fibers in mice has been identified by MDA-supported scientists in France. The new cells, dubbed “PICs,” may play at least as important a role in muscle regeneration and repair as satellite cells, which have been recognized as stemlike cells in muscle since the 1960s. As such, PICs could have implications for treatment of various forms of muscular dystrophy.
Hidden in what was previously thought to be solely connective tissue, PICs have the capacity to mature into skeletal muscle fibers or satellite cells, or they can replace themselves, at a higher rate than satellite cells can.
Investigators, led by David Sassoon, Giovanna Marazzi and Edgar Gomes at Pierre and Marie Curie University in Paris, conducted experiments in mice that demonstrated the presence of these previously unrecognized cells, which can give rise to satellite cells, muscle tissue or more of themselves, and that can repair damaged muscle. The findings were announced online Jan. 31, 2010, in Nature Cell Biology. Sassoon and Gomes received MDA support for this study.
The cells are located in the interstitium, the area between muscle fibers, and are partly defined by this location as “interstitial cells” — the “IC” in PIC.
They’re also defined by their production of a protein called PW1 and their lack of production of a protein called PAX7. (The presence or absence of these two proteins accounts for the “P” in PIC.) However, to become muscle, PICs require PAX7, a protein produced by satellite cells, in their immediate environment.
In mice, the PICs, like satellite cells, were plentiful at birth and then, also like satellite cells, became less plentiful two to three weeks later. The investigators say the PICs and the satellite cells may be recruited for muscle growth in these early weeks of life.
When the researchers injected purified PICs into injured leg muscles of mice and compared them with the actions of injected satellite cells, they found the PICs participated as efficiently as satellite cells in forming muscle fibers. The PICs, however, also generated many additional PICs, prompting the researchers to term this new cell type a “highly self-renewing stem cell.”
If PICs like those found in mice also exist and play a similar role in humans, they could become the targets of small-molecule-based therapies or used for cell transplantation in the treatment of muscular dystrophies.
Remodeling a building usually requires some degree of dismantling before new construction can begin. That principle, it now seems, also may apply to the remodeling of the body’s cells.
Scientists at Ottawa Hospital Research Institute and the University of Ottawa have recently found that it applies to muscle cells, which can only develop from a stemlike state into mature muscle fibers after a certain amount of their DNA has been disassembled and then rebuilt.
MDA grantee Lynn Megeney, a senior scientist at Ottawa Hospital Research Institute and an associate professor in the Departments of Medicine and Cellular and Molecular Biology at the University of Ottawa, led the investigative team, which conducted experiments on mouse muscle cells and published its findings online Feb. 16, 2010, in Proceedings of the National Academy of Sciences USA.
In 2002, Megeney and his team found that immature muscle cells called myoblasts could not become mature muscle cells if they were deprived of an enzyme called caspase 3. The finding was puzzling, because caspase 3 is normally associated with cell death.
The new experiments have revealed that caspase 3 activates another enzyme, caspase-activated DNase, or CAD, which causes controlled breaks at specific points along strands of DNA, followed by DNA repair.
Without caspase 3 and CAD, there are no such DNA strand breaks, no subsequent DNA repair, and no development of mature muscle cells.
“Our research suggests that when a gene is damaged, it can actually increase the expression [activity] of that gene, as long as the damage is repaired quickly,” Megeney said. “This is a novel way for a gene to become activated. We’ve shown that this process is crucial for the development of new muscle tissue, but we believe it may be important for the development of most other tissues as well.”
|Regular cardiac monitoring is recommended for people with DMD and for carriers of these MDs.|
Specific mutations in the dystrophin gene that predict whether heart muscle weakness (cardiomyopathy) will occur earlier or later in the course of Becker muscular dystrophy (BMD) have been identified by doctors at Ohio State University and Nationwide Children’s Hospital in Columbus, Ohio, as well as Washington University in St. Louis and the University of Utah in Salt Lake City.
The findings may help with predicting the disease course and may shed light on the complex mechanisms underlying cardiac degeneration in BMD or Duchenne muscular dystrophy (DMD), diseases caused by mutations in the dystrophin gene. The findings may prove useful in developing earlier and perhaps better treatments for this type of problem.
Federica Montanaro at Nationwide Children’s Hospital coordinated a multicenter team that included several MDA-associated physicians. Findings were published in the December 2009 issue of Circulation: Cardiovascular Genetics. Although MDA did not fund this study directly, several of the study’s authors are longtime MDA-associated clinicians and/or research grantees.
The researchers studied the dystrophin gene mutations and the clinical medical records of 78 people with either BMD-associated cardiomyopathy or X-linked dilated cardiomyopathy (a type of cardiomyopathy caused by dystrophin mutations that affect the heart, not skeletal muscle). DMD patients were not part of this study.
They found that different mutations could cause the median age at the onset of cardiomyopathy to range from the mid-20s to the mid-40s.
Families affected by BMD or DMD who would like to be part of an ongoing study to determine the relationship between disease course and specific dystrophin mutations can enroll in the United Dystrophinopathy Project, an ongoing study funded by the National Institutes of Health. See the United Dystrophinopathy Project and the Online Duchenne and Becker Muscular Dystrophy Patient Registry at https://www.dystrophin.org/dystrophin/index.php.
New findings show that the loss of a protein called MBNL2, which becomes trapped in the web of extra genetic material in cells affected by type 1 myotonic muscular dystrophy (MMD1, or DM1), may be a key cause of the weakness and muscle atrophy seen in this disease.
Scientists have previously identified similar entrapment of a protein called MBNL1 and attributed the myotonia (difficulty relaxing muscles) and abnormal muscle growth associated with MMD1 to loss of MBNL1’s normal functions.
The new findings were published online Jan. 24, 2010, in Nature Structural and Molecular Biology, by a team coordinated by Manuel Ares at the University of California-Santa Cruz. Although not specifically funded for this project, Ares has current MDA funding for MMD research.
The research adds to the accumulating knowledge about MMD1, and experts say replacing or freeing entrapped proteins like MBNL1 and MBNL2 could become treatment strategies.
New findings strongly suggest that oculopharyngeal muscular dystrophy (OPMD) can’t be explained solely on the basis of the formation of potentially toxic protein clumps in muscle cells, although this phenomenon may well be part of the problem. (See “Scientists prevent toxic protein clumps,” Research Updates, July-September 2009.)
A team that included MDA grantee Grace Pavlath at Emory University in Atlanta published new findings online Dec. 24, 2009, in Human Molecular Genetics, supporting the idea that a loss of function of the protein known as PABPN1, and not simply its accumulation in clumps, is key to understanding this disease. Therapies aimed solely at reducing the clumps may not be sufficient to treat OPMD.
|A normal function of hte PABPN1 protein may be to help attach protective "tails" to pieces of RNA in cell nuclei.||In OPMD, PABPN1 protein molecules are slightly longer than normal and may fail to help attach the required RNA tails.|
|Traditionally, SMA has been thought of as resulting from problems in the nerve cells, while CMT has been considered a disease of the axons (fibers) or the myelin coating surrounding each fiber. New findings show that rare forms of SMA, like CMT, can arise from abnormalities in nerve fibers.|
Three teams of researchers in the United States and Europe have identified specific mutations in a chromosome-12 gene for the TRPV4 protein that tie together the origins of type 2C Charcot-Marie-Tooth disease (CMT2C) and two rare forms of spinal muscular atrophy (SMA).
The results are surprising, as SMA and CMT typically arise from very different causes. SMA is considered a disease of the motor neurons in the spinal cord, while CMT is a disease of the peripheral nerve fibers. SMA usually is caused by mutations in the SMN gene on chromosome 5. CMT can be caused by mutations in any of more than 20 different genes.
Increased understanding of additional mechanisms involved in CMT and SMA may point the way toward new therapeutic targets and will almost certainly lead to improvements in diagnosis.
The new findings, detailed in three papers published online Dec. 27, 2009, in the journal Nature Genetics, identify two mutations in the TRPV4 protein that can cause CMT2C, one that causes scapuloperoneal SMA, and one that causes congenital distal SMA.
The TRVP4 protein is a cellular channel (tunnel) present in a variety of tissues, including nerve fibers, that opens and closes to allow calcium and other positively charged particles to move into and out of cells.
The newly identified mutations result in malfunctions of TRVP4. These malfunctions appear to cause abnormalities of calcium concentration (too high or too low, depending on the mutation) in the nerve fibers.
The findings, which are somewhat unexpected, unify the underlying mechanisms of CMT2C and both the targeted rare forms of SMA, showing that they all arise from abnormalities in the nerve fibers. Traditionally, SMA has been thought of as primarily resulting from problems in the cell bodies that reside in the spinal cord, not the fibers (axons) in the periphery; while on the other hand, CMT is traditionally thought of as a peripheral nerve disease.
Study team member Henry Houlden, a neurologist at University College London in the United Kingdom, holds a current MDA grant for studies in type 1A CMT. A number of former MDA grantees also contributed to the work.
A multinational team of researchers from Canada and Europe has identified specific mutations in the anoctamin 5 (ANO5) gene on chromosome 11 that can cause type 2L limb-girdle muscular dystrophy (LGMD2L) and type 3 Miyoshi myopathy. MDA supported Bernard Brais at the University of Montreal for this work.
The results are intriguing, as they describe one of a limited number of cases in which mutations in the same gene can cause more than one muscle disorder. Mutations in the ANO5 gene can cause limb-girdle muscular dystrophy (LGMD), which is characterized as proximal, affecting muscles near to the center of the body (the “limb girdles”); or Miyoshi myopathy, which is characterized as distal, affecting muscles far from the center of the body.
The findings could help scientists’ understanding of the biology of both types of muscle disease, lead to improvements in diagnostic testing, and ultimately lead to therapy development.
MDA-supported researchers at the University of Ottawa and Ottawa Hospital Research Institute (OHRI) have identified a biological pathway that may prove useful in developing treatments for spinal muscular atrophy (SMA).
Most treatment development for this disease focuses on increasing the production or viability of a protein called SMN. However, the experimental treatment the Ottawa researchers tried takes a completely different approach, one that the researchers say could provide an addition or alternative to SMN enhancement.
MDA grantee Rashmi Kothary at OHRI and the University of Ottawa coordinated the research team, which published its findings online Feb. 16, 2010, in Human Molecular Genetics.
Kothary and colleagues built on earlier research showing that, in addition to the loss of motor neurons, abnormalities of the neuromuscular junctions — the meeting points of nerve and muscle fibers — also are a feature of SMA and are a likely contributor to disease symptoms. They decided to see if they could improve the health of the neuromuscular junctions, regardless of SMN protein levels.
First, they showed that depletion of SMN leads to an increase in the activation of a protein called RHOA, followed by an increase in the activation of a protein called ROCK and a lack of stable, mature neuromuscular junctions.
They then found that, when they gave a compound that blocks ROCK activity to mice with SMN gene defects and an SMA-like disease, the mice had better-looking neuromuscular junctions and larger muscle fibers than did their untreated counterparts, and they survived much longer and moved around their cages much better than did the untreated rodents.
The mice in these experiments had approximately 15 percent of the normal level of SMN protein and generally died within one month of birth. The mice treated with a compound called Y27632, which blocks the ROCK protein, survived for at least three months after birth, with some surviving more than eight months.
Researchers note that the beneficial effect of Y27632 in their SMA mice is not due to SMN “rescue” but to “biological rescue, bypassing the SMN defect altogether.”
|Louis Ptacek (standing) has received MDA support for periodic paralysis research.|
The rare condition thyrotoxic hypokalemic periodic paralysis (TPP) causes people with normal muscle strength to experience episodes of paralysis and weakness. Until recently, TPP was known to be associated with attacks of high thyroid hormone secretion (thyrotoxicosis), but new information shows that in some cases the condition also has a genetic component — mutations in a newly identified potassium channel called KIR2.6 that helps control the flow of potassium ions into and out of muscle fibers.
“TPP may be a genetically conditioned disorder unmasked by thyrotoxicosis,” reported Louis Ptacek at the University of California-San Francisco, and colleagues, Jan. 8, 2010, in the journal Cell. In other words, in some instances, TPP requires a combination of nongenetic and genetic factors to make itself known. The nongenetic factor is high circulating thyroid hormone (thryrotoxicosis), and the genetic factor is an abnormality in a type of potassium channel that exists in muscle fibers.
Ptacek, though not funded by MDA for this study, has received significant MDA funding for other studies of periodic paralysis.