The overall goal of my research program is to identify mechanisms regulating organismal growth potential, with specific interest on mechanisms allowing for continual growth throughout an organism’s life (indeterminate growth). My lab addresses this goal using many approaches that range from cellular to organismal: molecular biology, cell biology, endocrinology, physiology, and morphology. Generally, my lab utilizes piscine species as model organisms because they offer diverse growth potentials and serve as excellent comparative platforms. The following projects are currently active and are being primarily driven by graduate and undergraduate students in my lab:
Epigenetic regulation of myogenesis is regulated by specific nutrients, namely amino acids.
Working closely with Dr. Jean-Charles Gabillard (INRA, Rennes, France) and Dr. Iban Seiliez (INRA, St. Pee, France) we have characterized the histone methylation profile related to pax7 and myogenin expression during in vitro myogenesis in Rainbow trout, an indeterminate growing fish. We recently also demonstrated that methionine depletion specifically alters this epigenetic profile, as well as reverts myoblasts to the quiescent state, suggesting a role of histone methylation in myogenic progression regulation. This quiescence appears to be reversible with addition of methionine. We are currently investigating the role of microRNAs as part of this mechanism as well.
Nutritional state regulates atrophy/hypertrophy balance in myogenic cells in vitro.
Working closely with Dr. Jean-Charles Gabillard (INRA, Rennes, France) and Dr. Iban Seiliez (INRA, St. Pee, France) we have characterized a novel in vitro model of amino acid depletion induced autophagy using zebrafish as a model organism. Using an amino acid depleted media, we can induce autophagy without apoptosis during myogenesis in vitro. We have characterized the histone methylation profiles affected by this cell phenotype switch and identified Atg4b, p62/sqstrm1, and lc3b as tightly regulated by starvation during the onset of autophagy.
Maternal nutritional transfer regulates growth via epigenetic mechanisms.
Working closely with Dr. Beth Cleveland (USDA, ARS, Leetown, WV USA) we have demonstrated that supplementing maternal broodstock diets with choline results in enhanced offspring growth performance. Also, we recently demonstrated that choline supplemented diet intake results in increased levels of choline into the pre-fertilized eggs. We hypothesized that maternal dietary intake regulates growth performance through changes in epigenetic mechanisms regulating growth. Choline serves as a methyl donor, and we are currently evaluating the role of choline supplementation on methylome changes.
The role of paired box transcription factors (Pax) in regulating myogenic stem cell populations.
My lab has recently demonstrated that indeterminate growing fish species exhibit a unique a pax3 expression profile in adult myogenic progenitor cells (MPCs; muscle stem cells) compared to determinate growing organisms. MPCs from adult indeterminate growing danios are pax3+/+, while determinate growing danios’ MPCs are pax3-/- (similar to adult mammalian MPCs) suggesting a potential role of pax3 in regulate MPC function. We are currently working to empirically test a role of pax3 in MPC function by knocking it down (morpholino and siRNA) in isolated MPCs.
Myogenic precursor cell contribution to muscle repair across the life-course in indeterminately growing species. Question: Does repair capacity decrease with age in indeterminate growing species?
We are currently characterizing the muscle repair program in indeterminately growing fish species (trout and danios) to establish a baseline understanding of the cells, genes, and pathways that play key roles in muscle repair in juvenile, sexually mature, and aged organisms. We hypothesize that species with high pax3 expression in MPCs as adults will have an enhanced repair capacity compared to species lacking pax3 expression as adults. Additionally, we will examine the role of growth hormone, IGF-I, IGF-II, and myostatin in muscle repair related to aging decline (or lack thereof).
The role of Teneurin C-terminal Associated Peptide (TCAP) in muscle function and metabolism during aging.
In collaboration with Dr. David Lovejoy (University of Toronto, Canada) and his PhD student Andrea D’Aquila we are investigating the conserved function of TCAP in muscle hypertrophy and metabolic control in teleosts. In addition, we have pilot funds from the Nathan Shock Center to examine the role TCAP plays in regulating muscle function decline during aging in the short-lived killifish model. We are also examining the effects of chronic TCAP treatment on zebrafish muscle hypertrophy and metabolic regulation. We will also begin evaluating the role TCAP plays in starvation-induced autophagy in primary myotubes in vitro. This work is specifically and uniquely informative for human muscular repair/regeneration and wasting disorders.
These research projects cover the general topic of mechanisms regulating muscle growth and repair, the overarching theme of my research program. This work is translatable to human health as mammals lose their ability to adequately repair their muscle tissue with age. In some teleost species, this functional decline in muscle structure and function is not observed and we hypothesize that the mechanisms that allow for continued growth throughout the lives of these organisms plays an important role in delaying muscle senescence (or wasting). In addition, improving adult muscle repair capabilities is extremely important in wound healing. In addition, this work is translatable to production agriculture, as further understanding of mechanisms regulating fish growth, from epigenetics to endocrinology, has direct applicability to the production efficacy to several finfish industries (including rainbow trout).
Comparative Growth Biology, Developmental Physiology, Diet-Epigenetic Interactions, Skeletal Muscle Growth Regulation, Science Community Outreach, k-12 Science Engagement
