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Genetic background and energetic demands from the environment determine the contractile properties of adult slow- and fast-twitch skeletal muscles. During early development, lineage is important in determining whether muscles become slow- or fast-twitch, but the properties of myofibers remain plastic and are later modified by activity (i.e., exercise). Transcription is the major mechanism determining the fiber type–specific properties of muscles; it regulates the expression of genes encoding contractile proteins and metabolic enzymes characteristic of slow and fast muscles. The troponin I slow (TnIs) and fast (TnIf) genes are selectively expressed in slow and fast muscles during development and are later regulated by distinct patterns of electrical impulses elicited by motor neurons. Using the TnI genes as a model system, we identified (SURE) and fast (FIRE) enhancers that regulate fiber type–specific transcription. We used reporter constructs driving the expression of either luciferase or GFP to map the transcription regulatory elements in SURE and FIRE.

We measured the effects of motor neuron electrical activity on TnI transcription in vivo by imaging individual myofibers. We determined the levels of transcription in adult muscles transfected with the SURE and FIRE GFP reporter constructs before and after electrical stimulation. We found that slow, tonic depolarization upregulated SURE transcription, whereas fast, phasic stimuli enhanced FIRE transcription. The results indicated that the TnI slow and fast enhancers sense and respond to distinct patterns of neuronal activity.

Next, we set out to identify the DNA elements and transcription factors that respond differentially to activity. Numerous lines of evidence indicate that the effects of activity are mediated by calcium, which is released from the sarcoplasmic reticulum after depolarization of the sarcolemma. Sustained low-frequency muscle depolarization causes a sustained elevation of calcium in the cell, whereas short depolarization bursts give rise to transient spikes of elevated calcium. NFAT and NFkB are two transcription factors that differentially respond to calcium transients in T cells in order to regulate genes differentially. Unexpectedly, we found that both transcription factors are also involved in the regulation of the TnI FIRE. Whereas NFAT repressed transcription from FIRE in response to slow-patterned activity, NFkB increased FIRE transcription in response to fast-patterned stimuli. These experiments exemplify how muscles can modify their adult contractile properties in response to distinct types of exercise.

 

Education

Ph.D.                                 Ph.D. in physiology and molecular biology

09/2003-02/2008                              Thesis title: Activity Dependent Regulation of

                                          the Gene Troponin Gene in Skeletal Muscle                                          

                                          Advisors:

                                          Dr. Andres Buonanno & Dr. Kristian Gundersen

                                      Section on Molecular Neurobiology,

                                          National Institute of Child Health and Human

                                          Development, NIH, Bethesda, MD.

 

Cand. Scient. (M.Sc.),       Thesis: Activity dependent gene regulation.

01/2000-12/2001(fall)                               Advisor: Prof. Kristian Gundersen

                                          Division of General Physiology, Dep. of Biology,
                                          University of Oslo, Oslo, Norway

 

02/2000                                                      Animal research Cat. C: Researchers who have 

                                          responsibility of leading of conducting animal 

                                          experiments.

                                          Dep. of Biology, University of Oslo.

 

Cand. Mag. (B.Sc.),           Dep. of Biology and Chemistry, University of Oslo

08/1995-12/1999

 

Military service.,                          Airforce Medical School, Stavern, Norway 

06/1997-05/1998

 

 

Professional Experience

Post. Doc (NFR)               Research on Heart failure

                                         Institute for Experimental Medical Research (IEMR) 

                                         Oslo University Hospital, Oslo, Norway

 

Post. Doc (NFR)               Research on negative and positive regulation of

08/2008-12/2011                        muscle promoters in response to changes in activity, 

                                         Department of Molecular Biosciences,

                                         University of Oslo, Oslo, Norway

 

Research scientist            Research on activity dependency in muscle                      

02/2008-08/2008                        Advisor: Prof. Kristian Gundersen

                                         Division of General Physiology, Dep. of Biology,

                                         University of Oslo

 

11/2000                                                    Research collaboration

                                         Advisor: Dr. Andres L. Buonanno

                                         Laboratory of Developmental Neurobiology,

                                         National Institutes of Health,

                                         Beteshda, Maryland

 

10/2000                                                    Co-teacher

                                         Dep. of Biology, University of Oslo, Oslo, Norway

 

10/1997-05/1998                                      Paramedical personnel

                                         Rygge Airforce Base, Rygge, Norway

 

Awards

Young Investigator Award 2007, The Scandinavian Physiological Society.

Young Investigator Award 2009, European Muscle Conferences.

Verv

1998-2000

-Medlem i Studieutvalget
-Varamedlem i instituttstyret
-Varamedlem i IT-komiteen ved Kjemisk instiutt, Universitetet i Oslo

Samarbeidspartner

Andres Buonanno, PhD, Head, Section on Molecular Neurobiology, National Institutes of Child Health and Human Development.

 

Emneord: NFAT, Skeletal muscle, Muscle activity

Publikasjoner

 

-Lunde, I. G., Anton, S. L., Bruusgaard, J. C., Rana, Z. A., Ellefsen, S. and Gundersen, K. 2011. Hypoxia inducible factor 1α links fast-patterned muscle activity and fast muscle phenotype in rats.J. Physiol (Epub ahead of print).

-Bruusgaard JC, Johansen IB, Egner IM, Rana, Z. A., Gundersen K. (2010). Myonuclei acquired by overload exercise precede hypertrophy and are not lost on detraining. PNAS107 (34),15111-6.

-Rana, Z. A.,Gundersen, K. and Buonanno, A. (2010). The ups and downs of gene regulation be electrical activity in skeletal muscles. J Muscle Res Cell Motil.Dec;30(7-8): 255-60. Review.

-Rana, Z. A., Gundersen, K. and Buonanno, A. (2008). Activity-Dependent Repression of Fast Muscle Genes by NFAT. PNAS 105 (15), 5921-5926.

-Ekmark, M., Rana, Z. A., Stewart, G., Hardie, D. G. & Gundersen K. 2007. De-phosphorylation of MyoD is linking nerve-evoked activity to fast myosin heavy chain expression in rodent adult skeletal muscle. J. Physiol 584 (2),637-50

-Lunde, I. G., Ekmark, M., Rana, Z. A., Buonanno, A. and Gundersen, K. 2007. PPARδ expression is influenced by muscle activity and induces slow muscle properties in adult rat muscles after somatic gene transfer.J. Physiol 582 (3),1277-87.

-Rana, Z. A., Gundersen, K., Buonanno A. & Vullhorst, D. 2005. Imaging Transcription in vivo: Distinct Regulatory Effects of Fast and Slow Activity Patterns on Promoter Elements from Vertebrate Troponin I Isoform Genes. J. Physiol 562 (3), 815-828.

-Rana, Z. A., Ekmark, M. & Gundersen K. 2004. Coexpression after electroporation of plasmid mixtures into muscle in vivo. Acta Physiol Scand 181(2), 233-238.

Publisert 4. nov. 2010 14:46 - Sist endret 10. jan. 2012 13:16