Irisin regulates cardiac physiology in zebrafish

PLOS ONE, Dec 2019

Irisin is a myokine encoded in its precursor fibronectin type III domain containing 5 (FNDC5). It is abundantly expressed in cardiac and skeletal muscle, and is secreted upon the activation of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1 alpha). We aimed to study the role of irisin on cardiac function and muscle protein regulation in zebrafish. Western blot analyses detected the presence of irisin protein (23 kDa) in zebrafish heart and skeletal muscle, and irisin immunoreactivity was detected in both tissues. Irisin siRNA treated samples did not show bands corresponding to irisin in zebrafish. In vitro studies found that treatment with irisin (0.1 nM) downregulated the expression of PGC-1 alpha, myostatin a, and b, while upregulating troponin C mRNA expression in zebrafish heart and skeletal muscle. Exogenous irisin (0.1 and 1 ng/g B.W) increased diastolic volume, heart rate and cardiac output, while knockdown of irisin (10 ng/g B.W) showed opposing effects on cardiovascular function. Irisin (1 and 10 ng/g B.W) downregulated PGC-1 alpha, myostatin a and b, and upregulated troponin C and troponin T2D mRNA expression. Meanwhile, knockdown of irisin showed opposing effects on troponin C, troponin T2D and myostatin a and b mRNAs in zebrafish heart and skeletal muscle. Collectively, these results identified muscle proteins as novel targets of irisin, and added irisin to the list of peptide modulators of cardiovascular physiology in zebrafish.

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Irisin regulates cardiac physiology in zebrafish

August Irisin regulates cardiac physiology in zebrafish Lakshminarasimhan Sundarrajan 0 1 Chanel Yeung 0 1 Logan Hahn 0 1 Lynn P. Weber 0 1 Suraj Unniappan 0 1 0 Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan , Saskatoon, Saskatchewan , Canada 1 Editor: Aldrin V. Gomes, University of California , Davis , UNITED STATES Irisin is a myokine encoded in its precursor fibronectin type III domain containing 5 (FNDC5). It is abundantly expressed in cardiac and skeletal muscle, and is secreted upon the activation of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1 alpha). We aimed to study the role of irisin on cardiac function and muscle protein regulation in zebrafish. Western blot analyses detected the presence of irisin protein (23 kDa) in zebrafish heart and skeletal muscle, and irisin immunoreactivity was detected in both tissues. Irisin siRNA treated samples did not show bands corresponding to irisin in zebrafish. In vitro studies found that treatment with irisin (0.1 nM) downregulated the expression of PGC-1 alpha, myostatin a, and b, while upregulating troponin C mRNA expression in zebrafish heart and skeletal muscle. Exogenous irisin (0.1 and 1 ng/g B.W) increased diastolic volume, heart rate and cardiac output, while knockdown of irisin (10 ng/g B.W) showed opposing effects on cardiovascular function. Irisin (1 and 10 ng/g B.W) downregulated PGC-1 alpha, myostatin a and b, and upregulated troponin C and troponin T2D mRNA expression. Meanwhile, knockdown of irisin showed opposing effects on troponin C, troponin T2D and myostatin a and b mRNAs in zebrafish heart and skeletal muscle. Collectively, these results identified muscle proteins as novel targets of irisin, and added irisin to the list of peptide modulators of cardiovascular physiology in zebrafish. Data Availability Statement; All relevant data are within the paper - Funding: This research was funded by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada. SU is a recipient of an Establishment Grant from the Saskatchewan Health Research Foundation (SHRF). The ultrasound machine was purchased using a Leaders Opportunities Fund from the Canada Foundation for Innovation (CFI) to Lynn Weber. The funders had no role in study design, data Introduction Skeletal muscle constitutes up to 40% of total body weight, and is considered an exercise dependent endocrine organ that constitutes approximately 75% of body proteins [ 1, 2 ]. Skeletal muscle regulates cytokines and myokines that exert autocrine and paracrine effects in humans [3±6]. Some of the skeletal muscle derived cytokines, including interleukin-6 have the ability to regulate glucose and lipid levels [7]. Irisin is a recently confirmed, exercise-induced, 23 kDa myokine abundantly expressed in rodent and human skeletal muscle [ 8 ]. Irisin is secreted from FNDC5, a 212 amino acid precursor, after the cleavage of its extracellular portion [ 9, 10 ]. FNDC5 is regulated by PGC-1 alpha, which forms an integral part of the muscle post-exercise, and causes an increase in energy expenditure in mammals [9]. Processing of FNDC5 by PGC-1 alpha triggers the release of irisin into circulation [ 9, 11 ]. FNDC5 mRNA is expressed in the brain, adipose tissue, gut (rectum) and pericardium in humans [12]. Previous collection and analysis, decision to publish, or preparation of the manuscript. results have reported that irisin is present in the cerebrospinal fluid and is expressed in the hypothalamus, adipose tissue and skeletal muscle in humans [ 13, 14 ]. Elevated levels of circulating irisin induced expression of thermogenin in white adipose cells, led to browning, and resulted in increased thermogenesis and energy expenditure [15]. Lower expression of FNDC5 has been associated with reduced aerobic performance in humans, contributing to heart failure [ 15 ]. Irisin is considered a key promoter in the central nervous system, and it regulates cardiac contractility [16±18]. More recently, irisin has gained importance as a potential biomarker for myocardial infarction due to its abundance in cardiac muscle [ 9, 19 ]. Irisin exhibits many biological actions in vertebrates. Immunohistochemical studies revealed irisin immunopositive cells concentrated in skeletal and cardiac muscles, Purkinje cells in cerebellum and neuroglial cells in rodents [ 20, 21 ]. Intracerebroventricular administration of irisin in rats resulted in increased blood pressure and enhanced cardiac contractility [17]. On the other hand, peripheral administration (intraperitoneal injection) of irisin, or irisin injection into the cerebellar area of the nucleus ambiguus decreased blood pressure via vagal stimulation in rats [ 17, 22 ]. It has been reported that overexpression of irisin increased energy expenditure, reduced body weight, improved lipid metabolism and (...truncated)


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Lakshminarasimhan Sundarrajan, Chanel Yeung, Logan Hahn, Lynn P. Weber, Suraj Unniappan. Irisin regulates cardiac physiology in zebrafish, PLOS ONE, 2017, Volume 12, Issue 8, DOI: 10.1371/journal.pone.0181461