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Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review with Cross-Species Comparisons

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Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review with Cross-Species Comparisons J Neuropathol Exp Neurol Vol. 75, No. 2, February 2016, pp. 102–110 doi: 10.1093/jnen/nlv020 REVIEW ARTICLE Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review With Cross-Species Comparisons Michael W. Lawlor, MD, PhD, Alan H. Beggs, PhD, Ana Buj-Bello, MD, PhD, Martin K. Childers, DO, PhD, James J. Dowling, MD, PhD, Emma S. James, PhD, Hui Meng, MD, PhD, Steven A. Moore, MD, PhD, Suyash Prasad, MBBS, MRCP, MRCPCH FFPM, Benedikt Schoser, MD, and Caroline A. Sewry, PhD From the Division of Pediatric Pathology, Department of Pathology and Lab- Downloaded from oratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin Abstract (MWL, HM); Division of Genetics and Genomics, The Manton Center X-linked myotubular myopathy (XLMTM) is a devastating, rare, for Orphan Disease Research, Boston Children’s Hospital, Harvard Med- congenital myopathy caused by mutations in the MTM1 gene, result- ical School, Boston, Massachusetts (AHB); Genethon, INSERM U951, ing in a lack of or dysfunction of the enzyme myotubularin. This Evry, France (ABB); Department of Rehabilitation Medicine, University leads to severe perinatal weakness and distinctive muscle pathology. of Washington, Seattle, Washington (MKC); Division of Neurology, http://jnen.oxfordjournals.org/ Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, It was originally thought that XLMTM was related to developmental Canada (JJD); Audentes Therapeutics, San Francisco, California (EJ, arrest in myotube maturation; however, the generation and characteri- SP); The University of Iowa, Carver College of Medicine, Department of zation of several animal models have significantly improved our un- Pathology, Iowa City, Iowa (SAM); Friedrich-Baur-Institute, Department derstanding of clinical and pathological aspects of this disorder. of Neurology, Ludwig-Maximilians-University Munich, Germany (BS); Dubowitz Neuromuscualar Centre, UCL Institute of Child Health/Great Myotubularin is now known to participate in numerous cellular pro- Ormond Street Hospital for Children, London, UK (CAS); and Wolfson cesses including endosomal trafficking, excitation-contraction cou- Centre for Inherited Neuromuscular Diseases, RJAH Orthopaedic Hospi- pling, cytoskeletal organization, neuromuscular junction structure, tal, Oswestry, UK (CAS) autophagy, and satellite cell proliferation and survival. The available Send correspondence to: Michael W. Lawlor, MD, PhD, 9000 W. Wisconsin vertebrate models of XLMTM, which vary in severity from complete Ave., TBRC Building, Room C4490, Milwaukee, WI 53226; E-mail: by guest on February 17, 2016 [email protected] absence to reduced functional levels of myotubularin, recapitulate This study was supported in part by funding from the National Institutes of features of the human disease to a variable extent. Understanding Health grants K08 AR059750, R01 AR044345, R21 AR064503, R01 how pathological endpoints in animals with XLMTM translate to hu- HL115001, and U54 NS053672, the Senator Paul D. Wellstone Muscular man patients will be essential to interpret preclinical treatment trials Dystrophy Cooperative Research Center, Seattle (NIH U54 AR065139), the Association Franc¸aise contre les Myopathies, the Muscular Dystro- and translate therapies into human clinical studies. This review sum- phy Association, the Joshua Frase Foundation, Cure CMD, Where marizes the published animal models of XLMTM, including those of There’s a Will, There’s a Cure Foundation, A Foundation Building zebrafish, mice, and dogs, with a focus on their pathological features Strength, the Peter Khuri Myopathy Research Foundation, and sponsored as compared to those seen in human XLMTM patients. research agreements with Audentes Therapeutics. Disclosures: Dr Lawlor is a member of the neuromuscular advisory board Key Words: Congenital, Centronuclear, Hypotrophy, Myopathy, for Audentes Therapeutics, and has been supported by sponsored re- Myotubular, Myotubularin, Sarcotubular. search agreements by Audentes Therapeutics. He is also a paid consul- tant for Sarepta Therapeutics and a scientific collaborator with Acceleron Pharma and Pfizer. Dr Beggs is an inventor of a patent for gene therapy in X-linked myotubular myopathy and a member of the sci- entific advisory Board of Audentes Therapeutics. Dr Buj-Bello is an in- INTRODUCTION ventor of a patent for gene therapy in X-linked myotubular myopathy and a scientific advisor for Audentes Therapeutics. Dr Childers is an in- X-linked myotubular myopathy (XLMTM) is a rare, dev- ventor on a patent for gene therapy in X-linked myotubular myopathy astating, congenital myopathy that mainly affects infants and and a member of the scientific advisory Board of Audentes Therapeutics. children. XLMTM is caused by mutations in the MTM1 gene, Drs. James and Prasad are employees and shareholders of Audentes the result of which is a loss of function of the myotubularin pro- Therapeutics. Dr Moore has fee-for-service consulting agreements with tein that leads to severe perinatal weakness and distinctive mus- Sarepta Therapeutics, Audentes Therapeutics, and Flagship Biosciences. Dr Schoser is a member of the neuromuscular advisory board for cle pathology. While “myotubular myopathy” was first thought Audentes Therapeutics. Dr Sewry is a member of the neuromuscular ad- to be related to a developmental arrest of myotube maturation visory board for Audentes Therapeutics. She is also a member of the edi- (1, 2), the generation and characterization of several animal torial boards of Neuromuscular Disorders, Muscle and Nerve, associate models over the past 15 years have led to significant advances editor for Neuropathology and Applied Neurobiology, and receives royal- ties for published books. Dr Dowling and Dr Meng have no relevant dis- in our understanding of this disorder. Myotubularin is known to closures. participate in numerous cellular processes including endosomal Supplementary Data can be found at http://www.jnen.oxfordjournals.org. trafficking, excitation-contraction coupling (ECC), cytoskeletal 102 VC 2016 American Association of Neuropathologists, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom- mons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] J Neuropathol Exp Neurol Volume 75, Number 2, February 2016 Cross-Species Comparison of XLMTM Pathology organization, neuromuscular junction structure, autophagy, and myotubularin is involved in the formation and maintenance of satellite cell proliferation and survival (3–7). Muscle-specific the “triad,” the set of juxtaposed sarcoplasmic reticulum (SR) knockdown of myotubularin in adult mice elicits similar pheno- and T-tubule structures responsible for mediating ECC (4, 5, 16, types, which indicates that myotubularin is essential for these 17). The severely disrupted architecture of the sarcotubular processes throughout life (8). The available vertebrate models of structures in XLMTM patients and myotubularin-deficient ani- XLMTM recapitulate features of the human disease to a variable mal models leads to abnormal Ca2þ exchange at the sarcotubu- extent. Understanding how pathological endpoints in myotubu- lar junction and impaired ECC. Studies of contractile function larin-deficient animals translate to human XLMTM patients will (4, 18) and myostatin inhibition therapy (19) in myotubularin- be essential for interpretation of preclinical studies of potential deficient mice suggest that this impairment of ECC is a major treatments and bridging therapies to the human clinical trial cause of weakness in XLMTM. Myotubularin also binds to des- stage. This review provides a summary of the published animal min and appears to control assembly of desmin intermediate fil- models of myotubularin deficiency with a focus on comparing aments (6); this interaction may contribute to the organelle mis- the pathological features of these models with those seen in localization observed in myotubularin-deficient muscle fibers. human XLMTM patients. These pathological abnormalities are Additionally, myotubularin deficiency produces abnormalities summarized in the Table. of the neuromuscular junction (3) and satellite cell numbers (8, 20, 21), which, in mouse models, likely contributes to progres- sive disease pathology and contractile dysfunction. Abnormali- KNOWN FUNCTIONS OF MYOTUBULARIN ties in the apoptotic, AKT/mTOR and ubiquitin-proteasome Myotubularin belongs to a family of 15 active and inac- pathways (8, 22, 23), have also been reported in multiple models Downloaded from tive phosphatases that act on phosphoinositides, which are lipid of myotubularin deficiency; these may further exacerbate the messengers that play important roles in membrane identity disease pathology and progression. and protein recruitment (9, 10). Through a common tyrosine phosphatase-like domain, active myotubularin family members dephosphorylate phosphatidylinositol 3-phosphate and phospha- PATHOLOGICAL FINDINGS IN HUMAN XLMTM http://jnen.oxfordjournals.org/ tidylinositol 3,5-bisphosphate, key regulators of membrane traf- The diagnosis of XLMTM is often strongly suggested by ficking and endocytosis (10, 11). The specificity of the different the histopathology observed in a muscle biopsy. The character- myotubularins for particular organelles, suborganelle domains,
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