Extensive morphological and immunohistochemical characterization in myotubular myopathy

Abstract

The X-linked myotubular myopathy (XLMTM) also called X-linked centronuclear myopathy is a rare congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM1-mutations according to the “adjusted-age” at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorganization of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers.

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

“…1 ), and ( 5 ) perinuclear vacuole-like areas ( 24 ). The central nuclei occur in both fiber types, and their frequencies range from as low as 5% ( 25 ) to greater than 50% ( 26 ). Central nuclei are often more common in myofibers expressing slow myosin and they can occur in fibers without developmental or fetal myosin, indicating that they have matured at least in terms of myosin expression.…”

“…Central nuclei are often more common in myofibers expressing slow myosin and they can occur in fibers without developmental or fetal myosin, indicating that they have matured at least in terms of myosin expression. All of these features are often seen in human XLMTM patient muscle at birth ( 26 ). Satellite cell numbers may be decreased in human XLMTM biopsies that have been taken as early as 30 weeks of gestational age ( 26 ); however, quantitation of satellite cells in human muscle can be difficult because factors such as muscle sampled and fiber typing have to be taken into account ( 26 ).…”

“…All of these features are often seen in human XLMTM patient muscle at birth ( 26 ). Satellite cell numbers may be decreased in human XLMTM biopsies that have been taken as early as 30 weeks of gestational age ( 26 ); however, quantitation of satellite cells in human muscle can be difficult because factors such as muscle sampled and fiber typing have to be taken into account ( 26 ). Necrosis, peri- and endomysial fibrosis, and inflammation are not features of XLMTM in any species.…”

Moving and positioning the nucleus in skeletal muscle – one step at a time

“…The movement of nuclei toward the periphery of myofibers (nuclear dispersion) may occur at 2 different periods of life in mammals: a) during mouse and human development, nuclei are centrally located and go to the periphery after birth, [70][71][72] b) after injury, centrally located nuclei move to the periphery which is part of the repair mechanism. 73,74 Nuclear dispersion is still under investigation but it is established that non-synaptic nuclei are not randomly distributed 47 suggesting the presence of specific factors involved in this process.…”

Avaliação não invasiva de modelos murinos para doenças musculares genéticas

“…Even with the very small sample sizes, either when exercise or when ischemia were applied as perturbation to the muscle physiology, a tendency of reduced muscle perfusion possibly combined to impaired energetic metabolism might be present in the heterozygous KI-Dnm2 R456W mouse. There are indications that myotubular myopathy patients, with mutation in MTM1, have reduced population of satellite cells, which would lead to impaired muscle regeneration (Shichiji et al, 2013). A similar reduction in the number of satellite cells is observed in the Mtm1-null mouse .…”