title: Skeletal muscle microRNA and messenger RNA profiling in cofilin-2 deficient mice reveals cell cycle dysregulation hindering muscle regeneration.
abstract: Congenital myopathies are rare skeletal muscle diseases presenting in early age with hypotonia and weakness often linked to a genetic defect. Mutations in the gene for cofilin-2 (CFL2) have been identified in several families as a cause of congenital myopathy with nemaline bodies and cores. Here we explore the global messenger and microRNA expression patterns in quadriceps muscle samples from cofillin-2-null mice and compare them with sibling-matched wild-type mice to determine the molecular pathways and mechanisms involved. Cell cycle processes are markedly dysregulated, with altered expression of genes involved in mitotic spindle formation, and evidence of loss of cell cycle checkpoint regulation. Importantly, alterations in cell cycle, apoptosis and proliferation pathways are present in both mRNA and miRNA expression patterns. Specifically, p21 transcript levels were increased, and the expression of p21 targets, such as cyclin D and cyclin E, was decreased. We therefore hypothesize that deficiency of cofilin-2 is associated with interruption of the cell cycle at several checkpoints, hindering muscle regeneration. Identification of these pathways is an important step towards developing appropriate therapies against various congenital myopathies.
authors: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics & Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors: Sarah U
authors: SU
authors: Morton
authors: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics & Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors: Mugdha
authors: M
authors: Joshi
authors: Division of Genetics & Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors: Talia
authors: T
authors: Savic
authors: Division of Genetics & Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors: Alan H
authors: AH
authors: Beggs
authors: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics & Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors: Pankaj B
authors: PB
authors: Agrawal
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002784:Cholesterol / Q000378:metabolism; D051340:Cofilin 2 / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D008938:Mitosis; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009135:Muscular Diseases / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D012038:Regeneration / Q000235:genetics*
chemical_list: D000199:Actins; C530105:Ccnd1 protein, mouse; C495816:Cfl2 protein, mouse; D051340:Cofilin 2; D019927:Cyclin E; D035683:MicroRNAs; D015513:Oncogene Proteins; D012333:RNA, Messenger; C568314:cyclin E1, mouse; D019938:Cyclin D1; D002784:Cholesterol