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Research
Laboratory of Muscle Stem Cells and Gene Regulation
Vittorio Sartorelli, M.D.
Chief, Laboratory of Muscle Stem Cells and Gene Regulation
Phone: (301) 435-8145
Fax: (301) 402-0009
E-mail: sartorev@mail.nih.gov
We are interested in elucidating the cellular and molecular mechanisms
governing proliferation and differentiation of skeletal muscle cells.
Role of acetyltransferases and the deacetylases in muscle transcription
and differentiation The p300 and PCAF acetyltransferases are
nodal coactivators of the muscle specific transcription factor MyoD. MyoD
is acetylated by PCAF resulting in an increased transcriptional activity.
Acetylation and deacetylation are in a dynamic equilibrium and we have
now begun to explore the role of nuclear deacetylases in controlling muscle
differentiation. Data generated in our laboratory indicate that the deacetylase
HDAC-1 counteracts the ability of MyoD to convert naïve fibroblasts to
muscle cells and impedes differentiation of cultured mouse myoblasts.
The molecular basis of this phenomenon correlates with the ability of
HDAC-1 to physically interact with and deacetylate both MyoD and histones
surrounding chromatin MyoD-binding sites in undifferentiated myoblasts.
Upon induction of cellular differentiation, the tumor suppressor protein
pRb is dephosphorylated, engages HDAC-1 and blocks transcription of genes
controlled by the transcription factor E2F and required for G1 progression.
During this process, HDAC-1 is physically displaced from MyoD to pRB allowing
acetylation of MyoD by the acetyltrasferases PCAF thereby promoting transcriptional
activation and cellular differentiation. We are now interested in defining
the cellular signals regulating the acetylase and deacetylase activities.
Expression profiling of skeletal muscle
cells exposed to small molecule inhibitors We have evaluated
the effects of global acetylation during muscle differentiation by employing
the specific deacetylase inhibitors (DI) sodium butyrate, trichostatin
A (TSA), and valproic acid (VPA). Our results indicate that mouse, human
myoblasts and mouse developing embryos exposed to a temporally defined
regimen of DI display a muscle hypertrophic response as judged by an increase
d expression of muscle-specific markers, multinucleation and increased
fiber diameter. To identify the molecules mediating the DI effects, we
have initiated an expression profiling of cells treated with TSA. We plan
to profile muscle gene expression in response to several small molecule
inhibitors.
Biochemical Characterization of Proteins
Associated with MyoD To isolate proteins interacting with MyoD
we have developed a bicistronic retroviral system for cellular delivery
of MyoD. Large quantities of cells are grown and protein purification
performed by affinity chromatography using FLAG-immobilized agarose beads.
The MyoD-associated factors (MAFs) are identified by mass spectrometry.
We have also generated cells expressing a version of MyoD that cannot
be acetylated and are interested in determining and compare the pattern
of the MAFs isolated using both MyoD 'wild-type' and non-acetylatable
MyoD.
Selected Publications
Fulco M, Cen Y, Zhao P, Hoffman EP, McBurney MW, Sauve AA, Sartorelli V. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell. 2008 May;14(5):661-73.
Di Padova M, Caretti G, Zhao P, Hoffman EP, Sartorelli V.
Myod acetylation influences temporal patterns of skeletal muscle gene expression.
J Biol Chem. 2007 Oct 27; [Epub ahead of print]
Caretti G., Schiltz R.L., Dilworth F.J., Di Padova M., Zhao P., Ogryzlo V., Fuller-Pace F., Hoffman E.P, Tapscott S.J., and Sartorelli V. The RNA helicases p68/p72 and the noncoding RNA SRA are coregulators of MyoD and skeletal muscle differentiation. Dev Cell. 2006; 11(4):547-60.
Minetti G.C., Colussi C., Adami R., Serra C., Mozzetta C., Parente V., Fortuni S., Straino S. , Sampaolesi M., Di Padova M., Illi B., Capogrossi M.C. , Sartorelli V., Bottinelli R., Gaetano C., Puri P.L. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med. 2006; 12(10):1147-50.
Iezzi S, Di Padova M, Serra C, Caretti G, Simone C, Maklan E, Minetti G, Zhao P, Hoffman EP, Puri PL, Sartorelli V. Deacetylase Inhibitors Increase Muscle Cell Size by Promoting Myoblast Recruitment and Fusion through Induction of Follistatin. Dev Cell. 2004; 6(5): 673-84.
See complete list of publications
Updated September 17, 2007
