You can assist researchers on a couple of issues in myotonic dystrophy. Read more about this ongoing study. (Posted in May 2019)
Studies of skeletal muscle and gastrointestinal dysfunction in myotonic dystrophy and controls
This study is designed to obtain data regarding 2 aspects of the phenotype in myotonic dystrophy (dystrophia myotonica or DM). These are multi-system diseases leading to symptoms in many regions of the body including skeletal muscles, central nervous system and the GI tract.
The aims of the study are two-fold: 1. to obtain physiological recordings of muscle contraction and motor unit activation in selected skeletal muscles to obtain possible outcome measures for future drug trials as well as understand the physiological underpinnings of motor dysfunction in these patients; 2. to study the role of the gut microbiome in relation to the gastro-intestinal dysfunction in DM patients.
Tasks to measure strength, fatigue, force and reaction time
Blood and stool samples
For more details about study procedures, please contact Stephen Gullet:
Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy that affects multiple organ systems. People with this condition develop progressive muscle wasting and weakness in their lower legs, hands, neck and face. Their muscles feel stiff and tight, causing them to be slow to relax certain muscles and therefore have difficulty releasing the hand from a handshake or a doorknob. In addition, people with this condition may have fatigue, muscle pain, difficulty swallowing, cataracts, irregularities in their heartbeat and respiratory complications. In his laboratory at Baylor College of Medicine, Dr. Thomas A. Cooper is leading the way to better understand this rare but devastating condition.
“Muscle wasting in this disease, which happens over decades, is responsible for the death of 60 percent of the patients,” said Cooper, who is professor of pathology and immunology, of molecular and cellular biology and of molecular physiology and biophysics at Baylor College of Medicine. “In this study we wanted to develop a novel model of the disease that would allow us to study muscle wasting in more detail.”
DM1 is caused by a striking expansion of three-letter repeats (CTG) in the DMPK gene. While the unaffected population carries 5 to 37 repeats, people with the condition have 50 to 3000 repeats. The RNA transcripts containing the CTG repeat expansion accumulate in the cell nucleus. This disturbs the normal cellular processing and distribution of molecules, such as muscleblind-like (MBNL) proteins, and induces up-regulation of others, such as the CELF1 protein. These alterations result in abnormal alternative splicing, which is thought to play a central role in the development of DM1. However, how these changes triggered by the expansion of the CTG repeat lead to muscle wasting still is not completely understood.
“We think that the current animal models of DM1 do not provide researchers with a complete and practical tool to investigate the mechanisms involved in muscle loss,” said Dr. Ginny Morriss, postdoctoral associate in the Cooper lab and the first author of this work. “This disease has many different components. Current animal models have some of the molecular components, but the physiological components, what’s happening to the tissue, are mostly missing. We wanted to develop a mouse modelof DM1 that clearly showed muscle loss and to implement a strategy that would allow us to study the pathways involved in muscle wasting.”
A mouse model of reversible DM1
The researchers genetically engineered a skeletal muscle-specific mouse model of DM1 that allowed them to induce the development of the disease at will. When induced, the mice expressed 960 CUG repeats of a particular region of the human DMPK gene and the RNA transcripts containing the CUG repeat expansion accumulated inside the cell nucleus triggering the chain of events that resulted in progressive muscle wasting. When the researchers ‘turned off’ the expression of the 960 CUG repeats, RNA accumulation and muscle loss progressively reverted.
In this model, the researchers saw alternative splicing that was consistent with findings in previous studies that correlated it with muscle weakness. They also validated signaling pathway changes that had been previously found by others. Importantly, they saw signaling pathway changes that had not been described before. These new changes stratified with how severe muscle wasting was in the mice, showing a clear association between specific signaling pathways and muscle loss.
“We validated the upregulation of the activity of protein AMPK-alpha, which had been shown previously by another group in another model. AMPK-alpha regulates the way the muscles metabolize and function,” Morriss said. “One of the new changes we discovered in our model was the dramatic reduction of signaling activity mediated by PDGFR-beta, which is involved in energy metabolism pathways.”
In addition, Cooper, Morriss and their colleagues found a connection with the human condition. They analyzed human tissue samples from patients and unaffected individuals and found in the patients the same signaling pathway changes they had found in their mouse model.
“The field has been focusing on alternative splicing. But, one of the things our findings tell us is that, although many of the characteristics of the disease result from alternative splicing defects, in addition there are other mechanisms at play and therefore other potential targets to treat this disease. There is more going on here than just alternative splicing,” said Cooper, who also is the S. Donald Greenberg and R. Clarence and Irene H. Fulbright Professor and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor.
“Now we have a mouse model in which we can test mechanisms involved in the disease. Because we made our model reversible, we can use it to test hypotheses about how the repeats cause the characteristics of the disease. We can systematically test each one of those hypothesis independently in our model blocking each signaling event specifically and determining how much that affects the disease. We can in this way determine how much each of the disease components, signaling pathways and alternative splicing, contribute to the disease,” Cooper said.
There is a new registry for Autism based at Univ California San Diego. This is called the Spark Program. 50% of children with myotonic dystrophy have some type of autism. I think that studying the autism in myotonic dystrophy would lead to some discovery of the genetic basis of autism.
If you or your child has a professional diagnosis of autism, you are eligible to participate in the SPARK research study!
What is SPARK? SPARK is the largest autism research project in US history, seeking to create a cohort of 50,00 individuals diagnosed with ASD and their biological family members. The entire autism community is encouraged to participate! There is NO cost to take part in SPARK. The research is sponsored by the Simons Foundation Autism Research Initiative (SFARI). We hope that this will lead to more insights of autism in myotonic dystrophy
Our Goal: Our goal is to build a community of 50,000 individuals with autism and their biological family members as we seek to speed up research and improve our understanding of autism — including learning what causes autism and how best to treat it. UCSD Autism Center of Excellence and over 25 of the nation’s leading medical schools and autism research centers are part of this effort. The entire autism community is encouraged to participate! There is NO cost to take part in SPARK.
What We Do: SPARK researchers extract genetic data through a saliva sample, and they study genes and information collected from thousands of people and their biological parents. At the same time, we aim to make participation as simple as possible, create an interconnected community, and share resources and information to our participants! We hope you will join us!
How to Join:
Sign-up online: here. It only takes 20 minutes. *If you are prompted with the question: Were you referred by a university, hospital, or registry? Please selectUCSD/SARRC.
Complete a few questionnaires online.
Provide a saliva sample. A saliva collection kit will be mailed to your home within 2-3 weeks after completing the registration. When you are done, simply mail it back to us for free.
Benefits of Joining:
If a genetic finding is discovered related to the cause of autism in a saliva sample, results will be shred back with families.
Individuals with autism will receive gift cards valued up to $50 for participating.
Families will have access to the latest research, articles, and monthly webinars featuring speakers from the autism community that provide useful information for families and diagnosed individuals.
The information you provide will help others with ASD in the future!
If you have any questions or would like to schedule an in-home appointment to complete the study, please contact our SPARK coordinator at (858) 534-6906 or SPARKForAutism@ucsd.edu.
Another paper has been published and revealed another potential treatment for myotonic dystrophy, Phenylbutazone PBZ.. Interestingly this study was also done in Japan………… now a hotbed of repositioning drugs for treatment of myotonic dystrophy. some info from the study
“Using the drug repositioning strategy, we found that PBZ markedly elevated MBNL1 expression in myogenic cells(Fig. 1 and Supplementary Fig. S1) as well as in skeletal muscles in HSALR mice model (Fig. 2 and Supplementary Fig. S2). PBZ mitigated muscle pathology (Fig. 2d,e) and improved the running wheel activity and grip strength in HSALR mice (Fig. 2c and Supplementary Fig. S2d).”
This summary above showed that in mice this drug helped mice with myotonic dystrophy run on the wheel better and had better grip strength. More info below
PBZ is an NSAID with anti-inflammatory, antipyretic, and analgesic activities. PBZ was approved in humans for rheumatoid arthritis and gout in 1949. Although incidental adverse effects of fatal liver disease and aplastic anemia markedly lowered the use of PBZ, PBZ is still used as an alternative drug for ankylosing spondylitis32,33.
Interestingly, another NSAID, ketoprofen has been reported to suppress CUG-induced lethality in Drosophila34, and we also found that 50 μ M ketoprofen upregulated the expression of Mbnl1 mRNA 1.2-fold in C2C12 cells, which was lower than the 1.3-fold increase of Mbnl1 mRNA by 50 μ M PBZ (Supplementary Fig. S6). Ketoprofen
and some other NSAIDs may have beneficial effects on a mouse model of DM1, as well as on DM1 patients.
Editors Note: This drug (PBZ) approval was removed for humans in 2003 in the USA and Canada. It is available for use in animals only. The drug Ketoprofen was not studied in depth but is an approved NSAZID drug in the USA. We have choosen the image of Ketoprofen as this is an approved drug in the USA.
Most of the emphasis on myotonic dystrophy has been on DM1 or Myotonic Dystrophy Type 1 Now a new generous gift will push the reseach front on DM2! A great day!
Gift Will Advance Research on Myotonic Dystrophy Type 2
September 09, 2014
Albert (Alfy) and Lilyan (Lil) Nathan
A $1.25 million gift from Lilyan (Lil) and Albert (Alfy) Nathan of Florida and Michael and Sherry Goldberg of Chicago will create a new center dedicated to research on myotonic dystrophy type 2 (DM2) at the University of Rochester School of Medicine and Dentistry. The gift will be used to support a new research program that will be led by UR Medicine neurologist Chad Heatwole, M.D.