Role of Insulin-Like Growth Factor Receptor 2 across Muscle Homeostasis: Implications for Treating Muscular Dystrophy

The insulin-like growth factor 2 receptor (IGF2R) plays a major role in binding and regulating the circulating and tissue levels of the mitogenic peptide insulin-like growth factor 2 (IGF2). IGF2/IGF2R interaction influences cell growth, survival, and migration in normal tissue development, and the deregulation of IGF2R expression has been associated with growth-related disease and cancer. IGF2R overexpression has been implicated in heart and muscle disease progression. Recent research findings suggest novel approaches to target IGF2R action. This review highlights recent advances in the understanding of the IGF2R structure and pathways related to muscle homeostasis

Chromatic sensitivity and tinted lenses: A preliminary study with the CAD test

The aim of this study was to assess the extreme effects of tinted lenses on colour vision by examining changes in chromatic sensitivity when viewing visual displays through a slightly tinted (“blue-blocking”) filter and through a heavily tinted, “orange” coloured filter. The CAD test was used to measure both red/green (RG) and yellow/blue (YB) chromatic sensitivity in ten subjects when viewing visual displays through each of the two filters. The measured RG and YB colour thresholds were then compared with similar measurements made without coloured filters in front of the eye. The blue-blocking filter absorbs only a small amount of short-wavelength light, whilst the “orange” filter preferentially attenuates more short-wavelength and some middle-wavelength light. The results show that the blue-blocking filter does not significantly affect either RG or YB colour vision. The orange filter, on the other hand, causes large changes in colour discrimination. The results were statistically analysed by comparing the results obtained with the coloured filters with those measured without any filters in front of the eye. More experimental work is now needed to establish how much short-wavelength light can be removed without significantly affecting the subject’s colour discrimination performance

Parkinson’s Disease in a Patient with 22q11.2 Deletion Syndrome: The Relevance of Detecting Mosaicisms by Means of Cell-By-Cell Evaluation Techniques

We report the case of a male patient from an Ashkenazi Jewish ethnic group with a history of midline defects (congenital heart disease, high-arched palate and bifid uvula). At the age of 46 years, he came to our center complaining of resting tremor, and a neurological examination concluded Parkinson?s disease. As a part of his approach, genetic evaluation was performed. Fluorescence in-situ hybridization (FISH) confirmed a mosaicism of a 22q deletion in 24% of the analyzed blood cells. Also, immunohistochemical studies were performed on samples from the minor salivary glands using a SNCA antibody. Intense SNCA immunoreactive profiles were obtained for cells from the salivary glands of the patient. This is, to our knowledge, the first description of the association of amosaicism of a 22q11.2 microdeletion syndrome with Parkinson?s disease. Our findings suggest that, before excluding the involvement of the 22q11.2 deletion in the etiology of early-onset PD cases, the spectrum of evaluations should be extended to include more sensitive FISH analysis and immunohistochemical studies. The pathogenesis of early-onset PD in patients with 22q11.2 deletion syndrome remains unknown but, if elucidated, it may contribute to understanding the etiology of PD and ultimately to preventionand treatment strategies.Fil: Perandones, Claudia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; ArgentinaFil: Farini, Veronica Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; ArgentinaFil: Pellene, L. A. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Sáenz Farret, Michel. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cuevas, S. M. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Micheli, Federico. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Radrizzani Helguera, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentin

Defective dystrophic thymus determines degenerative changes in skeletal muscle.

In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-β and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance

Clinical variability at the mild end of BRAT1-related spectrum: Evidence from two families with genotype–phenotype discordance

Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal to neurodevelopmental disorder, and cerebellar atrophy with or without seizures, without obvious genotype-phenotype associations. We describe two families at the mildest end of the spectrum, differing in clinical presentation despite a common genotype at the BRAT1 locus. Two siblings displayed nonprogressive congenital ataxia and shrunken cerebellum on magnetic resonance imaging. A third unrelated patient showed normal neurodevelopment, adolescence-onset seizures, and ataxia, shrunken cerebellum, and ultrastructural abnormalities on skin biopsy, representing the mildest form of NEDCAS hitherto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skippings. The p53-MCL test revealed normal ATM kinase activity. Our findings broaden the allelic and clinical spectrum of BRAT1-related disease, which should be suspected in presence of nonprogressive cerebellar signs, even without a neurodevelopmental disorder

Preliminary evidences of safety and efficacy of flavonoids- and omega 3-based compound for muscular dystrophies treatment: a randomized double-blind placebo controlled pilot clinical trial.

Background: Nutritional compounds can exert both anti-inflammatory and anti-oxidant effects. Since these events exacerbate the pathophysiology of muscular dystrophies, we investigated nutraceutical supplementation as an adjuvant therapy in dystrophic patients, to low costs and easy route of administration. Moreover, this treatment could represent an alternative therapeutic strategy for dystrophic patients who do not respond to corticosteroid treatment. Objective: A 24 weeks randomized double-blind placebo-controlled clinical study was aimed at evaluating the safety and efficacy of daily oral administration of flavonoidsand omega3-based natural supplement (FLAVOMEGA) in patients affected by muscular dystrophy with recognized muscle inflammation. Design: We screened 60 patients diagnosed for Duchenne (DMD), Facioscapulohumeral (FSHD), and Limb Girdle Muscular Dystrophy (LGMD). Using a computer-generated random allocation sequence, we stratified patients in a 2:1:1 ratio (DMD:FSHD:LGMD) to one of two treatment groups: continuous FLAVOMEGA, continuous placebo. Of 29 patients included, only 24 completed the study: 15 were given FLAVOMEGA, 14 placebo. Results: FLAVOMEGA was well tolerated with no reported adverse events. Significant treatment differences in the change from baseline in 6 min walk distance (6MWD; secondary efficacy endpoint) (P = 0.033) and in isokinetic knee extension (P = 0.039) (primary efficacy endpoint) were observed in LGMD and FSHD subjects. Serum CK levels (secondary efficacy endpoint) decreased in all FLAVOMEGA treated groups with significant difference in DMD subjects (P = 0.039). Conclusions: Although the small number of patients and the wide range of disease severity among patients reduced statistical significance, we obtained an optimal profile of safety and tolerability for the compound, showing valuable data of efficacy in primary and secondary endpoints

Inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling mediates delayed myogenesis in Duchenne muscular dystrophy fetal muscle

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder characterized by muscle wasting and premature death. The defective gene is dystrophin, a structural protein, absence of which causes membrane fragility and myofiber necrosis. Several lines of evidence showed that in adult DMD patients dystrophin is involved in signaling pathways that regulate calcium homeostasis and differentiation programs. However, secondary aspects of the disease, such as inflammation and fibrosis development, might represent a bias in the analysis. Because fetal muscle is not influenced by gravity and does not suffer from mechanical load and/or inflammation, we investigated 12-week-old fetal DMD skeletal muscles, highlighting for the first time early alterations in signaling pathways mediated by the absence of dystrophin itself. We found that PLC/IP3/IP3R/Ryr1/Ca2+ signaling is widely active in fetal DMD skeletal muscles and, through the calcium-dependent PKCa protein, exerts a fundamental regulatory role in delaying myogenesis and in myofiber commitment. These data provide new insights into the origin of DMD pathology during muscle development

Blockade of IGF2R improves muscle regeneration and ameliorates Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a debilitating fatal X-linked muscle disorder. Recent findings indicate that IGFs play a central role in skeletal muscle regeneration and development. Among IGFs, insulinlike growth factor 2 (IGF2) is a key regulator of cell growth, survival, migration and differentiation. The type 2 IGF receptor (IGF2R) modulates circulating and tissue levels of IGF2 by targeting it to lysosomes for degradation. We found that IGF2R and the store-operated Ca2+ channel CD20 share a common hydrophobic binding motif that stabilizes their association. Silencing CD20 decreased myoblast differentiation, whereas blockade of IGF2R increased proliferation and differentiation in myoblasts via the calmodulin/calcineurin/NFAT pathway. Remarkably, anti-IGF2R induced CD20 phosphorylation, leading to the activation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and removal of intracellular Ca2+. Interestingly, we found that IGF2R expression was increased in dystrophic skeletal muscle of human DMD patients and mdx mice. Blockade of IGF2R by neutralizing antibodies stimulated muscle regeneration, induced force recovery and normalized capillary architecture in dystrophic mdx mice representing an encouraging starting point for the development of new biological therapies for DMD