Projects
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
, Head, Section on Molecular Neurobiology, National Institutes of Child Health and Human Development.