Identification of Potentially Relevant Genes for Excessive Exercise-Induced Pathological Cardiac Hypertrophy in Zebrafish

Abstract

Exercise-induced cardiac remodeling has aroused public concern for some time, as sudden cardiac death is known to occur in athletes; however, little is known about the underlying mechanism of exercise-induced cardiac injury. In the present study, we established an excessive exercise-induced pathologic cardiac hypertrophy model in zebrafish with increased myocardial fibrosis, myofibril disassembly, mitochondrial degradation, upregulated expression of the pathological hypertrophy marker genes in the heart, contractile impairment, and cardiopulmonary function impairment. High-throughput RNA-seq analysis revealed that the differentially expressed genes were enriched in the regulation of autophagy, protein folding, and degradation, myofibril development, angiogenesis, metabolic reprogramming, and insulin and FoxO signaling pathways. FOXO proteins may be the core mediator of the regulatory network needed to promote the pathological response. Further, PPI network analysis showed that pik3c3, gapdh, fbox32, fzr1, ubox5, lmo7a, kctd7, fbxo9, lonrf1l, fbxl4, nhpb2l1b, nhp2, fbl, hsp90aa1.1, snrpd3l, dhx15, mrto4, ruvbl1, hspa8b, and faub are the hub genes that correlate with the pathogenesis of pathological cardiac hypertrophy. The underlying regulatory pathways and cardiac pressure-responsive molecules identified in the present study will provide valuable insights for the supervision and clinical treatment of pathological cardiac hypertrophy induced by excessive exercise.

Exercise, programmed cell death and exhaustion of cardiomyocyte proliferation in aging zebrafish

“…Both our data and that of Singleman and Holtzman (2012) also show a linear relationship with body length and ventricular length. However, although the Zhu group ( Zhou et al, 2020 ) also demonstrated the same ratio as us, 0.4 mm cm −1 at 24 and 36 months, it was 0.3 mm cm −1 from 6 to 12 months. Thus, overall, the 6-month-old fish represent the growth phase of young sexually mature individuals, the equivalent of humans in their second decade, and the 21-month-old fish represent the post-reproductive midlife phase after ∼50 years ( Cohen, 2018 ).…”

“…However, other studies have questioned this indeterminate growth pattern ( Sun et al, 2015 ; Biga and Goetz, 2006 ). Furthermore, it is not known whether the zebrafish heart has an indeterminate growth pattern, although it is recognised that the myocardial response to physiological stimulus is predominantly through hyperplasia ( Sarantis et al, 2019 ) rather than hypertrophy ( Hendricks et al, 2009 ; Zhou et al, 2020 ). Taken together, zebrafish would appear to be a tractable model for studying the proliferative response of cardiomyocytes during normal aging and in response to physiological stimuli, such as exercise.…”

Zebrafish Heart Failure Models

“…Thus, while unable to model HF, this model is relevant for investigating cardiac remodeling. However, others report zebrafish exercise-induced cardiomegaly to result from hypertrophy, oblivious to the possibility of cardiac hyperplasia ( Zhou et al, 2020 ). The authors also describe notable cardiac contractile impairment in the exercised fish.…”

“…The authors also describe notable cardiac contractile impairment in the exercised fish. However, no data on this is presented ( Zhou et al, 2020 ). The effects of exercise have been studied in a zebrafish cardiac cryoinjury model ( Rovira et al, 2018 ).…”

Identification of Potentially Related Genes and Mechanisms Involved in Skeletal Muscle Atrophy Induced by Excessive Exercise in Zebrafish

“…The zebrafish were randomly divided into two groups, both fed normally: the control group ( n = 30) and the excessive exercise group ( n = 30). The excessive exercise conditions were set up as described previously [ 26 ]. In brief, the excessive exercise group was forced to swim in a water current at a speed equivalent to 80% critical swimming speed (U crit, 24 cm/s) for 4 weeks (6 h for 6 days per week).…”