Awards - 2010

2010

NEW INVESTIGATOR RECOGNITION

The Lymn Foundation made awards of $500 each to new investigators for presenting posters that contributed new insights and understanding of biological or disease processes in skeletal muscle during the the recent conference on research developments in muscle biology: “Skeletal Muscle Satellite and Stem Cells.”  A committee of leaders at the conference recommended the investigators.

2010 AWARD RECIPIENTS

Skeletal Muscle Satellite and Stem Cells

(https://secure.faseb.org/faseb/meetings/Summrconf/Programs/11665.pdf)

Malea Murphy

Recent Interactions between satellite cells and connective tissue fibroblasts are critical for muscle regeneration

Department of Human Genetics, University of Utah

Colin Crist 

MicroRNA regulation of Pax3 and Myf5 during skeletal muscle differentiation 

CNRS URA 2578, Department of Developmental Biology, Paris, France

2010 ABSTRACTS

Distinct origins and genetic programs of head muscle satellite cells

Murphy MM, Lawson JA, Hutcheson DA, Kardon G 

Department of Human Genetics
University of Utah

Vertebrate muscle has a remarkable capacity for regeneration. Regeneration is largely mediated by satellite cells, which must become activated, proliferate, and differentiate to repair damaged myofibers. Interactions with the surrounding muscle connective tissue are likely to be important for muscle regeneration. The muscle connective tissue is composed largely of extracellular matrix (ECM) embedded within which are a small number of fibroblasts that produce the ECM. This connective tissue enwraps muscle, maintaining muscle structural integrity and transmitting muscle contractile force to adjoining tendon and bone. During muscle regeneration there is an increase in connective tissue ECM, termed fibrosis, which maintains the structure of the damaged muscle and may be an important source of signals regulating satellite cells. However, excessive connective tissue ECM can inhibit muscle regeneration. To characterize the interactions between muscle and its connective tissue during muscle regeneration, we have determined the temporal and spatial relationship between satellite cells, connective tissue fibroblasts, myofiber regeneration, and fibrosis after muscle injury. We find that after injury satellite cells and connective tissue fibroblasts expand in concert in regions that are enriched in regenerating myofibers and connective tissue fibrosis. Additionally, using mouse genetics we have tested the role of satellite cells and connective tissue fibroblasts in muscle regeneration. We find that these cell populations coordinately regulate each other and are critical for muscle regeneration. 

MicroRNA regulation of Pax3 and Myf5 during skeletal muscle differentiation 

Crist CG, Montarras D, Daubas P, Pallafacchina G, Rocancourt D, Cumano A, Conway SJ and Buckingham M 

CNRS URA 2578, Department of Developmental Biology; INSERM U668, Department of Immunology, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.; Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 USA 

Skeletal muscle stem cells are regulated by Pax3/7. During development, Pax3 is required for the maintenance of these cells in the somite and their migration to sites of myogenesis where Pax3 is down-regulated and myogenic determination factors such as Myf5, MyoD and Mrf4 are up-regulated. Continued expression of Pax3 interferes with muscle cell differentiation, both in the embryo and the adult.
Quantitative fine-tuning of Pax3 is critical and microRNAs provide a potential mechanism. We identify microRNA-27b, that directly targets the 3’UTR of Pax3 mRNA, as such a regulator. MiR-27b is expressed in the differentiating skeletal muscle of the embryonic myotome and in activated satellite cells of adult muscle. In vivo overexpression of a miR-27b transgene in Pax3 positive cells in the embryo leads to down-regulation of Pax3, resulting in interference with progenitor cell migration and in premature differentiation. In a complementary experiment, miR-27b inhibitors were transfected into cultures of adult muscle satellite cells that normally express miR-27b at the onset of differentiation, when Pax3 protein levels undergo rapid down-regulation. Interference with miR-27b function results in continuing Pax3 expression leading to more proliferation and a delay in the onset of differentiation. Pax7 levels are not affected. Introduction of miR-27b antagomirs at a site of muscle injury in vivo also affects Pax3 expression and regeneration in vivo. We therefore conclude that miR-27b regulates Pax3 protein levels and this down-regulation ensures rapid and robust entry into the myogenic differentiation program (1).
In addition, we also demonstrate that post-transcriptional regulation of Myf5 gene expression involves miR-31 repression acting through the Myf5-3’UTR. This regulation occurs in cases of inappropriate Myf5 transcription in the brain (2) as well as quantitative fine-tuning of Myf5 protein levels in activated satellite cells of adult skeletal muscle.

1. Crist et al. (2009) Muscle stem cell behaviour is modified by microRNA-27 regulation of Pax3 expression. Proc. Natl. Acad. Sci. U.S.A. 106, 13383-13387.

2. Daubas P. and Crist C. et al. (2009) The regulatory mechanisms that underlie inappropriate transcription of the myogenic determination gene Myf5 in the central nervous system. Dev. Biol. 327, 71-82.