Role of TGF-β signaling in inherited and acquired myopathies

The transforming growth factor-beta (TGF-β) superfamily consists of a variety of cytokines expressed in many different cell types including skeletal muscle. Members of this superfamily that are of particular importance in skeletal muscle are TGF-β1, mitogen-activated protein kinases (MAPKs), and myostatin. These signaling molecules play important roles in skeletal muscle homeostasis and in a variety of inherited and acquired neuromuscular disorders. Expression of these molecules is linked to normal processes in skeletal muscle such as growth, differentiation, regeneration, and stress response. However, chronic elevation of TGF-β1, MAPKs, and myostatin is linked to various features of muscle pathology, including impaired regeneration and atrophy. In this review, we focus on the aberrant signaling of TGF-β in various disorders such as Marfan syndrome, muscular dystrophies, sarcopenia, and critical illness myopathy. We also discuss how the inhibition of several members of the TGF-β signaling pathway has been implicated in ameliorating disease phenotypes, opening up novel therapeutic avenues for a large group of neuromuscular disorders

Congenital muscular dystrophies: New aspects of an expanding group of disorders

AbstractThe congenital muscular dystrophies comprise a genetically and clinically heterogeneous group of disorders characterized by early onset of progressive muscle weakness and often involvement of other organ systems such as the brain and eyes. During the last decade, significant progress has been made to further characterize various forms of congenital muscular dystrophies based on their specific genetic and clinical appearance. This review represents an overview of the recent accomplishments as they relate to clinical, diagnostic, pathogenetic and therapeutic aspects of congenital muscular dystrophies

Respiratory Failure Secondary to Human Metapneumovirus Requiring Extracorporeal Membrane Oxygenation in a 32-Month-Old Child

Human metapneumovirus (HMPV) is a common virus that can cause respiratory problems ranging from mild upper respiratory tract disease to respiratory failure requiring mechanical support. Here, we report a case of a 32-month-old male with a previous history of asthma, who developed respiratory failure two weeks after onset of cough and rhinorrhea and required extracorporeal membrane oxygenation (ECMO) for 9 days after failing high-frequency oscillatory ventilation (HFOV). To our knowledge, this is the oldest reported pediatric patient with respiratory failure secondary to human metapneumovirus that did not respond to mechanical ventilation. This case highlights three critical points: the potentially fatal causative role of HMPV in respiratory failure in an older pediatric age group of immunocompetent hosts, the importance of early recognition of impending respiratory failure, and the timely utilization of ECMO

Chandra X-Ray Observatory Observations of the Globular Cluster M71

We observed the nearby, low-density globular cluster M71 (NGC 6838) with the Chandra X-ray Observatory to study its faint X-ray populations. Five X-ray sources were found inside the cluster core radius, including the known eclipsing binary millisecond pulsar (MSP) PSR J1953+1846A. The X-ray light curve of the source coincident with this MSP shows marginal evidence for periodicity at the binary period of 4.2 h. Its hard X-ray spectrum and luminosity resemble those of other eclipsing binary MSPs in 47 Tuc, suggesting a similar shock origin of the X-ray emission. A further 24 X-ray sources were found within the half-mass radius, reaching to a limiting luminosity of 1.5 10^30 erg/s (0.3-8 keV). From a radial distribution analysis, we find that 18+/-6 of these 29 sources are associated with M71, somewhat more than predicted, and that 11+/-6 are background sources, both galactic and extragalactic. M71 appears to have more X-ray sources between L_X=10^30--10^31 erg/s than expected by extrapolating from other studied clusters using either mass or collision frequency. We explore the spectra and variability of these sources, and describe the results of ground-based optical counterpart searches.Comment: 36 pages including 7 figures and 8 tables, accepted by The Astrophysical Journa

Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function

Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (P = 0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered

Anti-CRISPR AcrIIA5 Potently Inhibits All Cas9 Homologs Used for Genome Editing

CRISPR-Cas9 systems provide powerful tools for genome editing. However, optimal employment of this technology will require control of Cas9 activity so that the timing, tissue specificity, and accuracy of editing may be precisely modulated. Anti-CRISPR proteins, which are small, naturally occurring inhibitors of CRISPR-Cas systems, are well suited for this purpose. A number of anti-CRISPR proteins have been shown to potently inhibit subgroups of CRISPR-Cas9 systems, but their maximal inhibitory activity is generally restricted to specific Cas9 homologs. Since Cas9 homologs vary in important properties, differing Cas9s may be optimal for particular genome-editing applications. To facilitate the practical exploitation of multiple Cas9 homologs, here we identify one anti-CRISPR, called AcrIIA5, that potently inhibits nine diverse type II-A and type II-C Cas9 homologs, including those currently used for genome editing. We show that the activity of AcrIIA5 results in partial in vivo cleavage of a single-guide RNA (sgRNA), suggesting that its mechanism involves RNA interaction

Disruption of the Sarcoglycan–Sarcospan Complex in Vascular Smooth Muscle A Novel Mechanism for Cardiomyopathy and Muscular Dystrophy

AbstractTo investigate mechanisms in the pathogenesis of cardiomyopathy associated with mutations of the dystrophin–glycoprotein complex, we analyzed genetically engineered mice deficient for either α-sarcoglycan (Sgca) or δ-sarcoglycan (Sgcd). We found that only Sgcd null mice developed cardiomyopathy with focal areas of necrosis as the histological hallmark in cardiac and skeletal muscle. Absence of the sarcoglycan–sarcospan (SG-SSPN) complex in skeletal and cardiac membranes was observed in both animal models. Loss of vascular smooth muscle SG-SSPN complex was only detected in Sgcd null mice and associated with irregularities of the coronary vasculature. Administration of a vascular smooth muscle relaxant prevented onset of myocardial necrosis. Our data indicate that disruption of the SG-SSPN complex in vascular smooth muscle perturbs vascular function, which initiates cardiomyopathy and exacerbates muscular dystrophy