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

Abstract

X-linked myotubular myopathy (XLMTM) is a devastating, rare, congenital myopathy caused by mutations in the MTM1 gene, resulting in a lack of or dysfunction of the enzyme myotubularin. This leads to severe perinatal weakness and distinctive muscle pathology. It was originally thought that XLMTM was related to developmental arrest in myotube maturation; however, the generation and characterization of several animal models have significantly improved our understanding of clinical and pathological aspects of this disorder. Myotubularin is now known to participate in numerous cellular processes including endosomal trafficking, excitation-contraction coupling, cytoskeletal organization, neuromuscular junction structure, autophagy, and satellite cell proliferation and survival. The available vertebrate models of XLMTM, which vary in severity from complete absence to reduced functional levels of myotubularin, recapitulate features of the human disease to a variable extent. Understanding how pathological endpoints in animals with XLMTM translate to human patients will be essential to interpret preclinical treatment trials and translate therapies into human clinical studies. This review summarizes the published animal models of XLMTM, including those of zebrafish, mice, and dogs, with a focus on their pathological features as compared to those seen in human XLMTM patients.

Long‐term effects of systemic gene therapy in a canine model of myotubular myopathy

“…In other sampled muscles from WT and XLMTM dogs, there was no evidence of organelle mislocalization or pathological myofiber smallness or internal nucleation. There were also occasional small fibers present in all dogs, consistent with our observation of the skeletal muscle histology of nondiseased dogs in this colony in prior studies . There was no evidence of inflammation, myonecrosis, myophagocytosis, myofiber regeneration, endomysial fibrosis, or fatty infiltration.…”

“…), with the exception of the 4 year, biceps brachii muscle of Turing. This specimen displayed myofiber smallness, internal nucleation, and organelle mislocalization consistent with XLMTM in a subset of fibers, and these changes were not apparent in the 3‐year biopsy from the same muscle . In other sampled muscles from WT and XLMTM dogs, there was no evidence of organelle mislocalization or pathological myofiber smallness or internal nucleation.…”

“…This specimen displayed myofiber smallness, internal nucleation, and organelle mislocalization consistent with XLMTM in a subset of fibers, and these changes were not apparent in the 3-year biopsy from the same muscle. 43 In other sampled muscles from WT and XLMTM dogs, there was no evidence of organelle mislocalization or pathological myofiber smallness or internal nucleation. There were also occasional small fibers present in all dogs, consistent with our observation of the skeletal muscle histology of nondiseased dogs in this colony in prior studies.…”

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

“…X‐linked myotubular myopathy (XLMTM) is a centronuclear myopathy caused by pathogenic variants in the MTM1 gene, resulting in a lack or dysfunction of the protein myotubularin . The disorder is rare and primarily affects boys, with an estimated incidence of 1 in 50,000 live male births .…”

Congenital myopathies: not only a paediatric topic

“…Some XLMTM carriers may develop mild weakness [55], sometimes very late in life [56], but more severe manifestations in females are usually due to skewed X-inactivation or additional X-chromosomal abnormalities [57,58]. There is a wide range of animal models of XLMTM with similar muscle pathology, summarized in a recent review [59].…”