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Loss of SMYD1 Results in Perinatal Lethality via Selective Defects within Myotonic Muscle Descendants.

ABSTRACT: SET and MYND Domain 1 (SMYD1) is a cardiac and skeletal muscle-specific, histone methyl transferase that is critical for both embryonic and adult heart development and function in both mice and men. We report here that skeletal muscle-specific, myogenin (myoG)-Cre-mediated conditional knockout (CKO) of Smyd1 results in perinatal death. As early as embryonic day 12.5, Smyd1 CKOs exhibit multiple skeletal muscle defects in proliferation, morphology, and gene expression. However, all myotonic descendants are not afflicted equally. Trunk muscles are virtually ablated with excessive accumulation of brown adipose tissue (BAT), forelimb muscles are disorganized and improperly differentiated, but other muscles, such as the masseter, are normal. While expression of major myogenic regulators went unscathed, adaptive and innate immune transcription factors critical for BAT development/physiology were downregulated. Whereas classical mitochondrial BAT accumulation went unscathed following loss of SMYD1, key transcription factors, including PRDM16, UCP-1, and CIDE-a that control skeletal muscle vs. adipose fate, were downregulated. Finally, in rare adults that survive perinatal lethality, SMYD1 controls specification of some, but not all, skeletal muscle fiber-types.

SUBMITTER: Rasmussen TL

PROVIDER: S-EPMC6473627 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Loss of SMYD1 Results in Perinatal Lethality via Selective Defects within Myotonic Muscle Descendants.

Rasmussen Tara L TL Tucker Haley O HO

Diseases (Basel, Switzerland) 20181220 1

SET and MYND Domain 1 (SMYD1) is a cardiac and skeletal muscle-specific, histone methyl transferase that is critical for both embryonic and adult heart development and function in both mice and men. We report here that skeletal muscle-specific, myogenin (myoG)-Cre-mediated conditional knockout (CKO) of Smyd1 results in perinatal death. As early as embryonic day 12.5, Smyd1 CKOs exhibit multiple skeletal muscle defects in proliferation, morphology, and gene expression. Howeve ...[more]

PMID: 30577454

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Project description:ObjectivesApoptosis-Inducing Factor (AIF) is a protein involved in mitochondrial electron transport chain assembly/stability and programmed cell death. The relevant role of this protein is underlined because mutations altering mitochondrial AIF properties result in acute pediatric mitochondriopathies and tumor metastasis. By generating an original AIF-deficient mouse strain, this study attempted to analyze, in a single paradigm, the cellular and developmental metabolic consequences of AIF loss and the subsequent oxidative phosphorylation (OXPHOS) dysfunction.MethodsWe developed a novel AIF-deficient mouse strain and assessed, using molecular and cell biology approaches, the cellular, embryonic, and adult mice phenotypic alterations. Additionally, we conducted ex vivo assays with primary and immortalized AIF knockout mouse embryonic fibroblasts (MEFs) to establish the cell death characteristics and the metabolic adaptive responses provoked by the mitochondrial electron transport chain (ETC) breakdown.ResultsAIF deficiency destabilized mitochondrial ETC and provoked supercomplex disorganization, mitochondrial transmembrane potential loss, and high generation of mitochondrial reactive oxygen species (ROS). AIF-/Y MEFs counterbalanced these OXPHOS alterations by mitochondrial network reorganization and a metabolic reprogramming toward anaerobic glycolysis illustrated by the AMPK phosphorylation at Thr172, the overexpression of the glucose transporter GLUT-4, the subsequent enhancement of glucose uptake, and the anaerobic lactate generation. A late phenotype was characterized by the activation of P53/P21-mediated senescence. Notably, approximately 2% of AIF-/Y MEFs diminished both mitochondrial mass and ROS levels and spontaneously proliferated. These cycling AIF-/Y MEFs were resistant to caspase-independent cell death inducers. The AIF-deficient mouse strain was embryonic lethal between E11.5 and E13.5 with energy loss, proliferation arrest, and increased apoptotic levels. Contrary to AIF-/Y MEFs, the AIF KO embryos were unable to reprogram their metabolism toward anaerobic glycolysis. Heterozygous AIF+/- females displayed progressive bone marrow, thymus, and spleen cellular loss. In addition, approximately 10% of AIF+/- females developed perinatal hydrocephaly characterized by brain development impairment, meningeal fibrosis, and medullar hemorrhages; those mice died 5 weeks after birth. AIF+/- with hydrocephaly exhibited loss of ciliated epithelium in the ependymal layer. This phenotype was triggered by the ROS excess. Accordingly, it was possible to diminish the occurrence of hydrocephalus AIF+/- females by supplying dams and newborns with an antioxidant in drinking water.ConclusionsIn a single knockout model and at 3 different levels (cell, embryo, and adult mice) we demonstrated that by controlling the mitochondrial OXPHOS/metabolism, AIF is a key factor regulating cell differentiation and fate. Additionally, by providing new insights into the pathological consequences of mitochondrial OXPHOS dysfunction, our new findings pave the way for novel pharmacological strategies.

Project description:Abstract BACKGROUND: Congenital Myotonic Dystrophy (CDM) is the harshest form of Myotonic Dystrophy type 1 (DM1,OMIM #160900). The mode of inheritance is autosomal dominant, and results from a microsatellite expansion in DMPK with an incidence of 2.1:1000,000 live births in Canada. The principal clinical signs during the neonatal period are myopathic facies, hypotonia and weakness resulting in such features as talipes equinovarus, nutritional, cardiac and respiratory problems. OBJECTIVES: To describe the main findings of CDM in the perinatal period. DESIGN/METHODS: A five year prospective cohort study from 2005 to 2010 of eligible incident cases of CDM was performed via the Canadian Pediatric Surveillance Program (CPSP). Reporting physicians completed a questionnaire with the medical history at birth and during the perinatal period. Our patients met the CDM criteria proposed by Campbell et al. (2013): 1) CDM symptoms with hospitalization greater of 72 hours; and 2) CTGrs above 200. RESULTS: We obtained 43 questionnaires, 22 female and 21 male (F:M ratio of 1.04:1). Average CTG repeat size (CGTrs) was 795.67 (250-2300). The main complication during the prenatal period was polyhydramnios (n=20). The majority of the patients (n=27) had full term pregnancy and with normal birth weight (n=25). Average Apgar was 4 at 1 (range 1-9), and 6 for 5 and 10. Intubation was required in 29/43 of the cases, with an average hospital stay of 43.5 days. Nutritional support (ie ng feeds) was required in 34/43, and it was longer than 14 days in 21 patients. Nine patients died, 6 of them due to respiratory failure. Four deaths were withdrawal of life support. CONCLUSION: The respiratory difficulties are well described as the principal complication in CDM (Ho et al. [2015]), but we found that the necessity of multiple nutritional interventions was the most frequent neonatal complication (79%), respiratory complications remains as the principal cause of death (66.6%). Zaki et al. (2010) describes a cohort with a 100% frequency of polyhydramnios, differing on ours where it is 46.5%. We conclude that CDM is not always evident prenatally by polyhydramnios, IUGR or preterm delivery. Nutritional and respiratory assessments should be prioritized, and nutritional interventions may extend for long periods of time. Despite high respiratory and feeding support needs, the majority of patients improved over time. Hence the importance of prenatal counseling and preparation for the complications in the neonatal period.

Dataset Information

Loss of SMYD1 Results in Perinatal Lethality via Selective Defects within Myotonic Muscle Descendants.

Publications

Loss of SMYD1 Results in Perinatal Lethality via Selective Defects within Myotonic Muscle Descendants.

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