PGC1α and Exercise Adaptations in Zebrafish

Abstract

Fish species display huge differences in physical activity ranging from lethargy to migration of thousands of miles, making them an interesting model to identify determinants of physical fitness. Here, we show a remarkable plasticity of zebrafish in response to exercise and induction of PGC1α (encoded by PPARGC1A), a dominant regulator of mitochondrial biogenesis. Forced expression of human PPARGC1A induces mitochondrial biogenesis, an exercise-like gene expression signature, and physical fitness comparable to wild-type animals trained in countercurrent swim tunnels. Quantifying transcriptional and proteomic changes in response to exercise or PGC1α, we identify conserved 'exercise' adaptations, including a stoichiometric induction of the electron transport chain (ETC) that re-organizes into respiratory supercomplexes in both conditions. We further show that ndufa4/ndufa4l, previously assigned to complex I, associates to free and supramolecular complex IV in vivo. Thus, zebrafish is a useful and experimentally tractable vertebrate model to study exercise biology, including ETC expression and assembly. HIGHLIGHTS PGC1α reprograms zebrafish skeletal muscle to a 'red fiber' phenotype and increases exercise performance  Zebrafish show a high molecular plasticity in response to PGC1α and exercise  SWATH-MS proteomics show a stoichiometric induction of the electron transport chain that organizes as supercomplexes in response to PGC1α and exercise

Generation of a zebrafish SWATH-MS spectral library to quantify 10,000 proteins

“…In contrast, muscle tissue contributed the lowest number of identifications reflecting the challenge of proteomic measurements in a tissue in which few highly abundant proteins make up most of the protein mass 33 . Nevertheless, we have recently shown the potential of measuring the proteome in such challenging tissues by characterizing exercise-induced changes in zebrafish muscle 34 . We thus envision the zebrafish SWATH spectral library to support and facilitate SWATH-MS studies in various tissues of this emerging model organism.…”

“…For example, ndufa4 is expressed in brain at a 3-fold higher level than ndufa4l, whereas ndufa4l is the dominant protein version expressed in liver and muscle. Ndufa4 is a member of the electron transport chain in mitochondria and we recently described that it interacts with respiratory supercomplexes in zebrafish 34 . The amino acids of ndufa4 and nduf4l are 73% and 68% conserved to the human NDUFA4 orthologue, but 24% of the amino acids differ among the two paralogues.…”

Mitochondria in Embryogenesis: An Organellogenesis Perspective

“…SCs enhance the stability of individual ETC complexes (Acin-Perez et al, 2008), increase electron transport efficiency and consequently limit reactive oxygen species (Genova and Lenaz, 2015; Cogliati et al, 2016). SCs have been reported in mature tissues in human, rodents and zebrafish (Lapuente-Brun et al, 2013; Greggio et al, 2017; Parisi et al, 2018). Their timing of appearance in embryogenesis is yet unknown.…”

A Reproducible Protocol to Measure the Critical Swimming Speed of Adult Zebrafish

“…Swimmill equipments. The absolute value of Ucrit measured in adult wild-type zebrafish (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) months old) appears to vary by the difference of the swimmill equipments. This is probably due to the size difference of swimming chamber that generates uneven water flow between center and peripheral.…”