RIPK3-mediated cell death is involved in DUX4-mediated toxicity in facioscapulohumeral dystrophy.

Background: Facioscapulohumeral dystrophy (FSHD) is caused by mutations leading to the aberrant expression of the DUX4 transcription factor in muscles. DUX4 was proposed to induce cell death, but the involvement of different death pathways is still discussed. A possible pro-apoptotic role of DUX4 was proposed, but as FSHD muscles are characterized by necrosis and inflammatory infiltrates, non-apoptotic pathways may be also involved.

Irregular Astigmatism Management Using SPOT Scleral Lenses in the Treatment of Corneal Ectasia and Penetrating Keratoplasty.

Purpose: To evaluate the outcome of SPOT scleral lenses in the management of irregular astigmatism in patients with corneal ectasia and penetrating keratoplasty. Second, we analyzed patients' characteristics and tolerance, comfort, and geometries of fitted lenses.

Method: Over a 5-year period, we included patients experiencing irregular astigmatism fitted with SPOT scleral contact lenses, from the University Hospital of Clermont-Ferrand, France.

A Deoxyribonucleic Acid Decoy Trapping DUX4 for the Treatment of Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral dystrophy (FSHD) is characterized by a loss of repressive epigenetic marks leading to the aberrant expression of the DUX4 transcription factor. In muscle, DUX4 acts as a poison protein though the induction of multiple downstream genes. So far, there is no therapeutic solution for FSHD.

One-hour universal protocol for mouse genotyping.

Background: Transgenic animals are widely used for research and for most of them, genotyping is unavoidable. Published protocols may be powerful but may also present disadvantages such as their cost or the requirement of additional steps/equipment. Moreover, if more than one strain must be genotyped, several protocols may need to be developed.

Targeting the Polyadenylation Signal of Pre-mRNA: A New Gene Silencing Approach for Facioscapulohumeral Dystrophy.

Facioscapulohumeral dystrophy (FSHD) is characterized by the contraction of the D4Z4 array located in the sub-telomeric region of the chromosome 4, leading to the aberrant expression of the DUX4 transcription factor and the mis-regulation of hundreds of genes. Several therapeutic strategies have been proposed among which the possibility to target the polyadenylation signal to silence the causative gene of the disease. Indeed, defects in mRNA polyadenylation leads to an alteration of the transcription termination, a disruption of mRNA transport from the nucleus to the cytoplasm decreasing the mRNA stability and translation efficiency.

Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches.

Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin.

Retinoic Acid Engineered Amniotic Membrane Used as Graft or Homogenate: Positive Effects on Corneal Alkali Burns.

Purpose: Alkali burns are the most common, severe chemical ocular injuries, their functional prognosis depending on corneal wound healing efficiency. The purpose of our study was to compare the benefits of amniotic membrane (AM) grafts and homogenates for wound healing in the presence or absence of previous all-trans retinoic acid (atRA) treatment.

Methods: Fifty male CD1 mice with reproducible corneal chemical burn were divided into five groups, as follows: group 1 was treated with saline solution; groups 2 and 3 received untreated AM grafts or grafts treated with atRA, respectively; and groups 4 and 5 received untreated AM homogenates or homogenates treated with atRA, respectively.

Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.

Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype 8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology, and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged life span to more than 1 year in the absence of toxicity or a humoral or cell-mediated immune response.

Site-specific Mtm1 mutagenesis by an AAV-Cre vector reveals that myotubularin is essential in adult muscle.

Manipulation of the mouse genome by site-specific mutagenesis has been extensively used to study gene function and model human disorders. Mouse models of myotubular myopathy (XLMTM), a severe congenital muscular disorder due to loss-of-function mutations in the MTM1 gene, have been generated by homologous recombination and shown that myotubularin is essential for skeletal muscle. However, since the Mtm1 deletion occurred constitutively or shortly after birth in these mice, it is not known whether myotubularin is required during adulthood, an important issue in the context of not only muscle biology but also therapies.

Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment.

X-linked myotubular myopathy is a severe congenital myopathy caused by deficiency of the lipid phosphatase, myotubularin. Recent studies of human tissue and animal models have discovered structural and physiological abnormalities in myotubularin-deficient muscle, but the impact of myotubularin deficiency on myogenic stem cells within muscles is unclear. In the present study, we evaluated the viability, proliferative capacity, and in vivo engraftment of myogenic cells obtained from severely symptomatic (Mtm1δ4) myotubularin-deficient mice.

Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models.

Myotubular myopathy (MTM) is a severe congenital muscle disease characterized by profound weakness, early respiratory failure and premature lethality. MTM is defined by muscle biopsy findings that include centralized nuclei and disorganization of perinuclear organelles. No treatments currently exist for MTM.

Regulation of the expression of the avian uncoupling protein 3 by isoproterenol and fatty acids in chick myoblasts: possible involvement of AMPK and PPARalpha?

The avian uncoupling protein 3 (UCP3), mainly expressed in muscle tissue, could be involved in fatty acid (FA) metabolism, limitation of reactive oxygen species production, and/or nonshivering thermogenesis. We recently demonstrated that UCP3 mRNA expression was increased by isoproterenol (Iso), a β-agonist, in chicken Pectoralis major. This upregulation was associated with changes in FA metabolism and variations in the activation of AMP-activated protein kinase (AMPK) and in the expression of the transcription factors peroxisome proliferator-activated receptor (PPAR)α, PPARβ/δ, and PPARγ coactivator-1α (PGC-1α).