Circulating microRNAs (miRNAs) are being considered as non-invasive biomarkers for disease progression and clinical trials. Congenital muscular dystrophy with deficiency of laminin α2 chain (LAMA2-CMD) is a very severe form of muscular dystrophy, for which no treatment is available. In order to identify LAMA2-CMD biomarkers we have profiled miRNAs in urine from the dy2J/dy2J mouse model of LAMA2-CMD at three distinct time points (representing asymptomatic, initial and established disease). We demonstrate that unique groups of miRNAs are differentially expressed at each time point. We suggest that urine miRNAs can be sensitive biomarkers for different stages of LAMA2-CMD.
Introduction: As the proportion of males with Duchenne muscular dystrophy (DMD) surviving into adulthood increases, more information is needed regarding their health care transition planning, an essential process for adolescents and young adults with DMD. The objective of this study was to describe the health care transition experiences of a population of males living with Duchenne or Becker muscular dystrophy (DBMD).
Methods: The eligible participants, identified through the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) surveillance project, were 16–31 years old and lived in Arizona, Colorado, Georgia, Iowa, or western New York (n=258). The MD STARnet Health Care Transitions and Other Life Experiences Survey was conducted in 2013 and administered online or in a telephone interview. Sixty-five males (25%) completed the survey. Among non-ambulatory males, response differences were compared by age group. Statistical comparisons were conducted using Fisher’s exact test, or when appropriate, the Chisquare test.
Results: Twenty-one percent of non-ambulatory males aged 16–18 years, 28% of non-ambulatory males aged 19–23 years, 25% of non-ambulatory males aged 24–30 years, and 18 ambulatory males had a written transition plan. Nineteen percent of non-ambulatory males aged 24–30 years had delayed or gone without needed health care in the past 12 months. Among non-ambulatory males aged 24–30 years, 75% had cardiology providers and 69% had pulmonology providers involved in their care in the past 12 months. Twentyeight percent of non-ambulatory males aged 19–23 years and 25% of non-ambulatory males aged 24–30 years reported that they did not receive health care or other services at least once because they were unable to leave their home. Non-ambulatory males aged 16–18 years (29%) were less likely to have ever discussed how to obtain or keep health insurance as they get older compared to non-ambulatory males aged 24-30 years (69%) (p <0.01).
Discussion: This study identified potential barriers to the successful health care transition of males with DBMD. The results of this study may indicate a lack of targeted informational resources and education focused on supporting the transition of young men with DBMD as they age from adolescence into adulthood within the healthcare system. Future studies could determine the reasons for the potential barriers to health care and identify the optimal transition programs for males with DBMD. There are a few online resources on transition available to adolescents and young adults with special health care needs.
Introduction Care Considerations supported by the Centers for Disease Control and Prevention for the management of Duchenne muscular dystrophy were published in 2010, but there has been limited study of implementation in the United States. Methods A questionnaire collecting information about standard care practices and perceived barriers was piloted by 9 clinic directors of facilities within the Muscular Dystrophy Surveillance, Tracking and Research network. Results Six clinic directors completed the questionnaire; 1 adult-only clinic was excluded. Over 80% adherence was found for 30 of 55 recommendations examined. Greatest variability was for initiation of corticosteroids, bone health monitoring, type of pulmonary function testing, and psychosocial management. Barriers included unclear guidelines, inadequate time and funding, family-specific barriers and lack of empirical support for some recommendations. Discussion This pilot study showed implementation of the 2010 Care Considerations, except for recommendations based largely on expert consensus. Complete adherence requires more studies and active promotion.
Introduction: Duchenne Muscular Dystrophy is a genetic disease that is caused by a deficiency of dystrophin protein. Both Duchenne Muscular Dystrophy patients and dystrophic mice suffer from intestinal dysfunction.
Methods: The present study arose from a chance observation of differences in fecal output of dystrophic vs. normal mice during 20minutes of forced continuous treadmill exercise. Here, we report on the effects of exercise on fecal output in two different dystrophic mutants and their normal background control strains. All fecal materials evacuated during exercise were counted, dried and weighed.
Results: Mice of both mutant dystrophic strains produced significantly more fecal material during the exercise bout than the relevant control strains.
Discussion: We propose that exercise-induced Colo-Rectal Activation Phenotype test could be used as a simple, highly sensitive, noninvasive biomarker to determine efficacy of dystrophin replacement therapies.
INTRODUCTION: Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder that causes progressive skeletal and cardiac muscle weakness in boys. Cardiac dysfunction is a frequent cause of death in DMD. Glucocorticoids are the standard of care in DMD. The long-term use of oral glucocorticoids in DMD is complicated by poor bone health. Epidemiological studies suggest a biological link between the loss of bone mineral density (BMD) and cardiovascular disease, including coronary artery and cerebrovascular diseases. Whether an association between low BMD and cardiac dysfunction occurs in DMD boys has not yet been studied. The objective of this retrospective cohort study was to examine the relationship between BMD and cardiovascular health in DMD.
METHODS: Retrospective data analyses was performed from de-identified medical records from a tertiary academic medical center. Whole body BMD was measured using dual-energy xray absorptiometry (DEXA) scan and left ventricular ejection fraction (LVEF) was measured using echocardiogram. Linear regression was used to evaluate the relationship between BMD and LVEF.
RESULTS: Data was analyzed from a total of 32 boys with DMD. The mean age at which baseline BMD measurements was obtained of 11±3 (SD) years. The worst LVEF was measured at a mean of 23.7±21.8 (SD) months after the baseline BMD measurement. The final adjusted linear regression of the relationship between baseline BMD z-score and worst LVEF was not statistically significant (ß=0.41, p‑value=0.6455).
DISCUSSION: In this cohort of boys with DMD, BMD was not associated with LVEF dysfunction up to 79 months later. Future research with a longer longitudinal follow-up period is warranted to evaluate the relationship between BMD and cardiovascular disease in DMD.
The dystrophinopathies (Duchenne [DMD] and Becker muscular dystrophy) are progressive diseases that until recently had no specific treatments. New FDA pathways to drug approval in rare diseases have resulted in a dramatic increase in the number of treatment trials for DMD and recently, two approved drugs. Health insurance policies for DMD products have been constructed with limited input from neuromuscular specialists directly involved in patient care and without patient input. These policies often reflect a lack of understanding of the disease, clinical population or the treatment. To ensure that policy determinations reflect best clinical practice, we recommend insurers work with neuromuscular specialists with expertise in care for patients with dystrophinopathy, as well as patients and families, and prominent advocacy organizations, such as Parent Project Muscular Dystrophy, in developing policies.
Muscular dystrophy (MD) describes generalized progressive muscular weakness due to the wasting of muscle fibers. The progression of the disease is affected by known immunological and mechanical factors, and possibly other unknown mechanisms. These dynamics have begun to be elucidated in the last two decades. This article reviews mathematical models of MD and models that could be used to study molecular and cellular components implicated in MD progression. A biological background for these processes is also presented. Molecular effectors that contribute to MD include mitochondrial bioenergetics and genetic factors; both drive cellular metabolism, communication and signaling. These molecular events leave cells vulnerable to mechanical stress which can activate an immunological cascade that weakens cells and surrounding tissues. This review article lays the foundation for a systems biology approach to study MD progression.
Histone acetyl transferases (HATs) and histone deacetylases (HDAC) control transcription during myogenesis. HDACs promote chromatin condensation, inhibiting gene transcription in muscle progenitor cells until myoblast differentiation is triggered and HDACs are released. HATs, namely CBP/p300, activate myogenic regulatory and elongation factors promoting myogenesis. HDAC inhibitors are known to improve regeneration in dystrophic muscles through follistatin upregulation. However, the potential of directly modulating HATs remains unexplored. We tested this possibility in a well-known zebrafish model of Duchenne muscular dystrophy. Interestingly, CBP/p300 transcripts were found downregulated in the absence of Dystrophin. While investigating CBP rescuing potential we observed that dystrophin-null embryos overexpressing CBP actually never show significant muscle damage, even before a first regeneration cycle could occur. We found that the pan-HDAC inhibitor trichostatin A (TSA) also prevents early muscle damage, however the single HAT CBP is as efficient even in low doses. The HAT domain of CBP is required for its full rescuing ability. Importantly, both CBP and TSA prevent early muscle damage without restoring endogenous CBP/p300 neither increasing follistatin transcripts. This suggests a new mechanism of action of epigenetic regulators protecting dystrophin-null muscle fibres from detaching, independent from the known improvement of regeneration upon damage of HDACs inhibitors. This study builds supporting evidence that epigenetic modulators may play a role in determining the severity of muscle dystrophy, controlling the ability to resist muscle damage. Determining the mode of action leading to muscle protection can potentially lead to new treatment options for muscular dystrophies in the future.
INTRODUCTION: Both genetic and infectious diseases can result in skeletal muscle degeneration, inflammation, pain, and/or weakness. Duchenne muscular dystrophy (DMD) is the most common congenital muscle disease. DMD causes progressive muscle wasting due to mutations in Dystrophin. Influenza A and B viruses are frequently associated with muscle complications, especially in children. Infections activate an immune response and immunosuppressant drugs reduce DMD symptoms. These data suggest that the immune system may contribute to muscle pathology. However, roles of the immune response in DMD and Influenza muscle complications are not well understood. Zebrafish with dmd mutations are a well-characterized model in which to study the molecular and cellular mechanisms of DMD pathology. We recently showed that zebrafish can be infected by human Influenza A virus (IAV). Thus, the zebrafish is a powerful system with which to ask questions about the etiology and mechanisms of muscle damage due to genetic and/or infectious diseases.
METHODS: We infected zebrafish with IAV and assayed muscle tissue structure, sarcolemma integrity, cell-extracellular matrix (ECM) attachment, and molecular and cellular markers of inflammation in response to IAV infection alone or in the context of DMD.
RESULTS: We find that IAV-infected zebrafish display mild muscle degeneration with sarcolemma damage and compromised ECM adhesion. An innate immune response is elicited in muscle in IAV-infected zebrafish: NFkB signaling is activated, pro-inflammatory cytokine expression is upregulated, and neutrophils localize to sites of muscle damage. IAV-infected dmd mutants display more severe muscle damage than would be expected from an additive effect of dmd mutation and IAV infection, suggesting that muscle damage caused by Dystrophin-deficiency and IAV infection is synergistic.
DISCUSSION: These data demonstrate the importance of preventing IAV infections in individuals with genetic muscle diseases. Elucidating the mechanisms of immune-mediated muscle damage will not only apply to DMD and IAV, but also to other conditions where the immune system, inflammation, and muscle tissue are known to be affected, such as autoimmune diseases, cancer, and aging.
Introduction: Duchenne Muscular Dystrophy (DMD) is a debilitating muscle wasting disorder with no cure. Safer supplements and therapies are needed to improve the severity of symptoms, as severe side effects are associated with the only effective treatment, corticosteroids. The amino acid taurine has shown promise in ameliorating dystrophic symptoms in mdx mice, an animal model of DMD, however little work is in 21-28 (d)ay animals, the period of natural peak damage.
Methods: This study compares the effect of prenatal taurine supplementation on tibialis anterior (TA) in situ contractile function, histopathological characteristics and the abundance of Ca2+-handling as well as pathologically relevant proteins in non-exercised mdx mice at 28 and 70 d.
Results: Supplementation elevated TA taurine content by 25% (p<0.05), ameliorated in situ specific force by 60% (p<0.05) and improved histological characteristics in 28 d mdx mice; however no benefit was seen in 70 d mice, where background pathology was initially stable. Age specific effects in SERCA1, calsequestrin 1 (CSQ1), CSQ2, utrophin and myogenin protein abundances were seen between both 28 and 70 d mdx and mdx taurine-supplemented mice.
Discussion: Considering these findings and that taurine is a relatively cost effective, readily accessible and side effect free dietary supplement, we propose further investigation into taurine supplementation during pregnancy in a protective capacity, reminiscent of folate in the prevention of spinal bifida.