PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

Sabha, Nesrin; Volpatti, Jonathan; Gonorazky, Hernan; Reifler, Aaron N.; Davidson, Ann E.; Li, Xingli; Eltayeb, Nadine; Dall’Armi, Claudia; Paolo, Gilbert Di; Brooks, Susan V.; Buj‐Bello, Ana; Feldman, Eva L.; Dowling, James J.

doi:10.1172/jci86841

Cited by 86 publications

(131 citation statements)

References 39 publications

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“…Indeed, mutations in the gene coding for the lipid phosphatase MTM1 cause X-linked myotubular myopathy (XLMTM), also known as centronuclear myopathy, likely by deregulating PtdIns3 P metabolism [47]. Indeed, it was shown that the disruption of the PIK3C2B kinase resulted in a complete prevention of the myopathy phenotypes in a Mtm1 disease mouse model, and inhibition of the PIK3C2B kinase activity after appearance of myopathy symptoms promoted a striking rescue in the zebrafish model [48]. …”

Section: Phosphatidylinositol 3-phosphate (Ptdins3p) An Endosomal mentioning

confidence: 99%

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

Craene

Bertazzi

Bär

et al. 2017

IJMS

171

149

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Abstract:Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and cytoskeleton dynamics. Although detected in small concentrations in membranes, their role is essential to cell function, since imbalance in their concentrations is a hallmark of many cancers. Their synthesis involves phosphorylating/dephosphorylating positions D3, D4 and/or D5 of their inositol ring by specific lipid kinases and phosphatases. This process is tightly regulated and specific to the different intracellular membranes. Most enzymes involved in phosphoinositide synthesis are conserved between yeast and human, and their loss of function leads to severe diseases (cancer, myopathy, neuropathy and ciliopathy).Keywords: lipids; membrane trafficking; vesicles; phosphoinositides; phosphatase; kinase Phosphoinositides in Cellular Membranes Lipids, Major Membrane ComponentsThe dynamic modulation of the physicochemical properties of membranes is required for eukaryotic cells function. Indeed, cells live in an environment characterized by temperature, relative humidity, pH, sun exposure, osmotic pressure and nutrient variations. Living organisms have to adapt to variations of these different factors in order to keep their intracellular balance. Eukaryotic cells have achieved this by adopting a compartmentalized organization, which minimizes the intracellular variations resulting from extracellular fluctuations. The plasma membrane is the first barrier separating the cytoplasm from the extracellular medium. Its composition ensures a mechanical protection, but also allows exchanges with the medium through transporters and receptors, as a form of very selective permeability.Membranes are composed of two phospholipid leaflets organized as a bilayer in which sterols, glycolipids and proteins are inserted. The phospholipids of this bilayer are amphiphilic with a hydrophilic group (head) linked to a hydrophobic group (tail) ( Figure 1A). In the bilayer, the hydrophobic groups face each other, thus creating a hydrophobic space in between them, which ensures its role as a barrier. This property is very important for the anchoring of hydrophobic molecules, such as sterols or ceramides, transmembrane domains or the lipid anchor of proteins. The lipid composition of membranes varies according to the organism (eukaryotes or prokaryotes), the cell type (among the different tissues of a multicellular organism), the membrane type (plasma Int.

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Section: Phosphatidylinositol 3-phosphate (Ptdins3p) An Endosomal mentioning

confidence: 99%

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

Craene

Bertazzi

Bär

et al. 2017

IJMS

171

149

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“…Disruption of PIP2 expression in C2C12 myoblasts, a myogenic cell line, with calcimycin, LiCl, neomycin, or genetic reduction of PIP5KIγ, reduced myoblast fusion suggesting PIP2 contributes to the fusogenic signaling pathway [14]. Additionally, manipulation of PIP3 levels improved the severe muscular dystrophy phenotype in myotubularin ( Mtm1 ) deficient mice and zebrafish [15]. Therefore, expression and localization of phosphoinositides serve as a lipid code to direct cellular activity, and a unique balance of lipids is required by muscle for proper function.…”

Section: Introductionmentioning

confidence: 99%

Muscle cell communication in development and repair

Demonbreun

McNally

2017

Current Opinion in Pharmacology

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Under basal conditions, postnatal skeletal muscle displays little cell turnover. With injury, muscle initiates a rapid repair response to reseal damaged membrane, reactivating many developmental pathways to facilitate muscle regeneration and prevent tissue loss. Muscle precursor cells become activated accompanied by differentiation and fusion during both muscle growth and regeneration; inter-cellular communication is required for successful completion of these processes. Cellular communication is mediated by lipids, fusogenic membrane proteins, and exosomes. Muscle-derived exosomes carry proteins and micro RNAs as cargo. Secreted factors such as IGF-1, TGFβ, and myostatin are also released by muscle cells providing local signaling cues to modulate muscle fusion and regeneration. Proteins that regulate myoblast fusion also participate in membrane repair and regeneration. Here we will review methods of muscle cell communication focusing on proteins that mediate membrane fusion, exosomes, and autocrine factors.

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“…15,16 Similarly, in a dog model of a naturally occurring MTM1 variant, 17 preclinical testing of a single intravascular dose of recombinant AAV8-MTM1 vector improved muscle weakness and respiratory impairment and prolonged life span through 4 years. 18,19 Other studies have suggested that myotubularin protein replacement, 19 down-regulation of dynamin 2 expression, 20,21 or inhibition of PIK3C2B 22 activity may be viable therapeutic strategies. With the start of the first clinical trials of a directed gene therapy for XLMTM this year, 23 there is a clear need for natural history information for this disease.…”

mentioning

confidence: 99%

A multicenter, retrospective medical record review of X‐linked myotubular myopathy: The recensus study

et al. 2017

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Introduction: X‐linked myotubular myopathy (XLMTM), characterized by severe hypotonia, weakness, respiratory distress, and early mortality, is rare and natural history studies are few. Methods: RECENSUS is a multicenter chart review of male XLMTM patients characterizing disease burden and unmet medical needs. Data were collected between September 2014 and June 2016. Results: Analysis included 112 patients at six clinical sites. Most recent patient age recorded was ≤18 months for 40 patients and >18 months for 72 patients. Mean (SD) age at diagnosis was 3.7 (3.7) months and 54.3 (77.1) months, respectively. Mortality was 44% (64% ≤18 months; 32% >18 months). Premature delivery occurred in 34/110 (31%) births. Nearly all patients (90%) required respiratory support at birth. In the first year of life, patients underwent an average of 3.7 surgeries and spent 35% of the year in the hospital. Discussion: XLMTM is associated with high mortality, disease burden, and healthcare utilization. Muscle Nerve 57: 550–560, 2018

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PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

Cited by 86 publications

References 39 publications

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

Muscle cell communication in development and repair

A multicenter, retrospective medical record review of X‐linked myotubular myopathy: The recensus study

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