cyclin-d1 and Muscular-Diseases

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.

Topics: Actins; Animals; Apoptosis; Cell Cycle; Cholesterol; Cofilin 2; Cyclin D1; Cyclin E; Gene Expression Regulation; Mice; Mice, Knockout; MicroRNAs; Mitosis; Muscle, Skeletal; Muscular Diseases; Oncogene Proteins; Regeneration; RNA, Messenger

Skeletal muscles adapt to increasing workload by augmenting their fiber size, through mechanisms that are poorly understood. This study identifies the cytokine interleukin-6 (IL-6) as an essential regulator of satellite cell (muscle stem cell)-mediated hypertrophic muscle growth. IL-6 is locally and transiently produced by growing myofibers and associated satellite cells, and genetic loss of IL-6 blunted muscle hypertrophy in vivo. IL-6 deficiency abrogated satellite cell proliferation and myonuclear accretion in the preexisting myofiber by impairing STAT3 activation and expression of its target gene cyclin D1. The growth defect was indeed muscle cell intrinsic, since IL-6 loss also affected satellite cell behavior in vitro, in a STAT3-dependent manner. Myotube-produced IL-6 further stimulated cell proliferation in a paracrine fashion. These findings unveil a role for IL-6 in hypertrophic muscle growth and provide mechanistic evidence for the contribution of satellite cells to this process.

Topics: Animals; Blotting, Western; Cell Line; Cell Movement; Cell Proliferation; Cyclin D1; Enzyme-Linked Immunosorbent Assay; Hypertrophy; Immunohistochemistry; Interleukin-6; Mice; Mice, Knockout; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Diseases; Myoblasts; Reverse Transcriptase Polymerase Chain Reaction; Satellite Cells, Skeletal Muscle; STAT3 Transcription Factor