Cardiac function in muscular dystrophy associates with abdominal muscle pathology.

Background: The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy.

Methods: Using a mouse model of limb girdle muscular dystrophy, the mouse, we compared muscle pathology across different muscle groups and heart.

Disruption of the lamin A and matrin-3 interaction by myopathic LMNA mutations.

The nuclear face of the nuclear membrane is enriched with the intermediate filament protein lamin A. Mutations in LMNA, the gene encoding lamin A, lead to a diverse set of inherited conditions including myopathies that affect both the heart and skeletal muscle. To gain insight about lamin A protein interactions, binding proteins associated with the tail of lamin A were characterized.

New approaches to establish genetic causality.

Cardiovascular medicine has evolved rapidly in the era of genomics with many diseases having primary genetic origins becoming the subject of intense investigation. The resulting avalanche of information on the molecular causes of these disorders has prompted a revolution in our understanding of disease mechanisms and provided new avenues for diagnoses. At the heart of this revolution is the need to correctly classify genetic variants discovered during the course of research or reported from clinical genetic testing.

Effect of Lidocaine on Swallowing During FEES in Patients With Dysphagia.

Purpose: The aims of this study were to assess the effects of 0.2 mL of 4% atomized lidocaine on swallowing and tolerability during Fiberoptic Endoscopic Evaluation of Swallowing (FEES).

Methods: A single blinded study was conducted with 17 dysphagic patients, who received 4 standardized boluses in 2 sequential FEES exams under 2 conditions: non-anesthetized (decongestant only) and anesthetized (lidocaine 4%+decongestant).

The genetic landscape of cardiomyopathy and its role in heart failure.

Heart failure is highly influenced by heritability, and nearly 100 genes link to familial cardiomyopathy. Despite the marked genetic diversity that underlies these complex cardiovascular phenotypes, several key genes and pathways have emerged. Hypertrophic cardiomyopathy is characterized by increased contractility and a greater energetic cost of cardiac output.

Dark-field transmission electron microscopy of cortical bone reveals details of extrafibrillar crystals.

In a previous study we showed that most of the mineral in bone is present in the form of "mineral structures", 5-6nm-thick, elongated plates which surround and are oriented parallel to collagen fibrils. Using dark-field transmission electron microscopy, we viewed mineral structures in ion-milled sections of cortical human bone cut parallel to the collagen fibrils. Within the mineral structures we observe single crystals of apatite averaging 5.

Protocol for the Femoroacetabular Impingement Trial (FAIT): a multi-centre randomised controlled trial comparing surgical and non-surgical management of femoroacetabular impingement.

Aims: Femoroacetabular Junction Impingement (FAI) describes abnormalities in the shape of the femoral head-neck junction, or abnormalities in the orientation of the acetabulum. In the short term, FAI can give rise to pain and disability, and in the long-term it significantly increases the risk of developing osteoarthritis. The Femoroacetabular Impingement Trial (FAIT) aims to determine whether operative or non-operative intervention is more effective at improving symptoms and preventing the development and progression of osteoarthritis.

Targeting latent TGFβ release in muscular dystrophy.

Latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) bind to inactive TGFβ in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGFβ release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region.

Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy.

Background: Cardiomyopathy is highly heritable but genetically diverse. At present, genetic testing for cardiomyopathy uses targeted sequencing to simultaneously assess the coding regions of >50 genes. New genes are routinely added to panels to improve the diagnostic yield.

Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice.

Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-β has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGFβ-dependent pathology have not been segregated. Here, we generated transgenic mice with myofiber-specific inhibition of TGFβ signaling owing to expression of a TGFβ type II receptor dominant-negative (dnTGFβRII) truncation mutant.

Excess SMAD signaling contributes to heart and muscle dysfunction in muscular dystrophy.

Disruption of the dystrophin complex causes muscle injury, dysfunction, cell death and fibrosis. Excess transforming growth factor (TGF) β signaling has been described in human muscular dystrophy and animal models, where it is thought to relate to the progressive fibrosis that characterizes dystrophic muscle. We now found that canonical TGFβ signaling acutely increases when dystrophic muscle is stimulated to contract.

The Boston Residue and Clearance Scale: preliminary reliability and validity testing.

Background: There is no appropriately validated scale with which to rate the problem of residue after swallowing. The Boston Residue and Clearance Scale (BRACS) was developed to meet this need. Initial reliability and validity were assessed.

GRAF1 promotes ferlin-dependent myoblast fusion.

Myoblast fusion (a critical process by which muscles grow) occurs in a multi-step fashion that requires actin and membrane remodeling; but important questions remain regarding the spatial/temporal regulation of and interrelationship between these processes. We recently reported that the Rho-GAP, GRAF1, was particularly abundant in muscles undergoing fusion to form multinucleated fibers and that enforced expression of GRAF1 in cultured myoblasts induced robust fusion by a process that required GAP-dependent actin remodeling and BAR domain-dependent membrane sculpting. Herein we developed a novel line of GRAF1-deficient mice to explore a role for this protein in the formation/maturation of myotubes in vivo.

P38α MAPK underlies muscular dystrophy and myofiber death through a Bax-dependent mechanism.

Muscular dystrophies are a group of genetic diseases that lead to muscle wasting and, in most cases, premature death. Cytokines and inflammatory factors are released during the disease process where they promote deleterious signaling events that directly participate in myofiber death. Here, we show that p38α, a kinase in the greater mitogen-activated protein kinase (MAPK)-signaling network, serves as a nodal regulator of disease signaling in dystrophic muscle.

Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair.

Many monogenic disorders, including the muscular dystrophies, display phenotypic variability despite the same disease-causing mutation. To identify genetic modifiers of muscular dystrophy and its associated cardiomyopathy, we used quantitative trait locus mapping and whole genome sequencing in a mouse model. This approach uncovered a modifier locus on chromosome 11 associated with sarcolemmal membrane damage and heart mass.

Genetic profiling for risk reduction in human cardiovascular disease.

Cardiovascular disease is a major health concern affecting over 80,000,000 people in the U.S. alone.

Exon-skipping therapy: a roadblock, detour, or bump in the road?

Exon skipping is a promising therapeutic for Duchenne muscular dystrophy patients, but the road to drug approvals is foggy and may require more early-stage derisking and regulatory guidance.

Abcc9 is required for the transition to oxidative metabolism in the newborn heart.

The newborn heart adapts to postnatal life by shifting from a fetal glycolytic metabolism to a mitochondrial oxidative metabolism. Abcc9, an ATP-binding cassette family member, increases expression concomitant with this metabolic shift. Abcc9 encodes a membrane-associated receptor that partners with a potassium channel to become the major potassium-sensitive ATP channel in the heart.

The CO-Regulation Database (CORD): a tool to identify coordinately expressed genes.

Background: Meta-analysis of gene expression array databases has the potential to reveal information about gene function. The identification of gene-gene interactions may be inferred from gene expression information but such meta-analysis is often limited to a single microarray platform. To address this limitation, we developed a gene-centered approach to analyze differential expression across thousands of gene expression experiments and created the CO-Regulation Database (CORD) to determine which genes are correlated with a queried gene.

Dynamin 2 the rescue for centronuclear myopathy.

Centronuclear myopathy is a lethal muscle disease. The most severe form of the disease, X-linked centronuclear myopathy, is due to mutations in the gene encoding myotubularin (MTM1), while mutations in dynamin 2 (DNM2) and amphiphysin 2/BIN1 (AMPH2) cause milder forms of myopathy. MTM1 is a lipid phosphatase, and mutations that disrupt this activity cause severe muscle wasting.

Supercomputing for the parallelization of whole genome analysis.

Motivation: The declining cost of generating DNA sequence is promoting an increase in whole genome sequencing, especially as applied to the human genome. Whole genome analysis requires the alignment and comparison of raw sequence data, and results in a computational bottleneck because of limited ability to analyze multiple genomes simultaneously.

Results: We now adapted a Cray XE6 supercomputer to achieve the parallelization required for concurrent multiple genome analysis.