Impacts of rat hindlimb Fndc5/irisin overexpression on muscle and adipose tissue metabolism

Author:

Farrash W.12,Brook M.1,Crossland H.1,Phillips B. E.1,Cegielski J.1,Wilkinson D. J.1,Constantin-Teodosiu D.3,Greenhaff P. L.3,Smith K.1,Cleasby M.4,Atherton P. J.1

Affiliation:

1. Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham National Institute for Health Research Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, United Kingdom

2. College of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia

3. Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom

4. Molecular Physiology of Diabetes Laboratory, Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, United Kingdom

Abstract

Myokines, such as irisin, have been purported to exert physiological effects on skeletal muscle in an autocrine/paracrine fashion. In this study, we aimed to investigate the mechanistic role of in vivo fibronectin type III domain-containing 5 (Fndc5)/irisin upregulation in muscle. Overexpression (OE) of Fndc5 in rat hindlimb muscle was achieved by in vivo electrotransfer, i.e., bilateral injections of Fndc5 harboring vectors for OE rats ( n = 8) and empty vector for control rats ( n = 8). Seven days later, a bolus of D2O (7.2 mL/kg) was administered via oral gavage to quantify muscle protein synthesis. After an overnight fast, on day 9, 2-deoxy-d-glucose-6-phosphate (2-DG6P; 6 mg/kg) was provided during an intraperitoneal glucose tolerance test (2 g/kg) to assess glucose handling. Animals were euthanized, musculus tibialis cranialis muscles and subcutaneous fat (inguinal) were harvested, and metabolic and molecular effects were evaluated. Muscle Fndc5 mRNA increased with OE (~2-fold; P = 0.014), leading to increased circulating irisin (1.5 ± 0.9 to 3.5 ± 1.2 ng/mL; P = 0.049). OE had no effect on protein anabolism or mitochondrial biogenesis; however, muscle glycogen was increased, along with glycogen synthase 1 gene expression ( P = 0.04 and 0.02, respectively). In addition to an increase in glycogen synthase activation in OE ( P = 0.03), there was a tendency toward increased glucose transporter 4 protein ( P = 0.09). However, glucose uptake (accumulation of 2-DG6P) was identical. Irisin elicited no endocrine effect on mitochondrial biogenesis or uncoupling proteins in white adipose tissue. Hindlimb overexpression led to physiological increases in Fndc5/irisin. However, our data indicate limited short-term impacts of irisin in relation to muscle anabolism, mitochondrial biogenesis, glucose uptake, or adipose remodeling.

Funder

MRC Versus Arthritis Centre for Musculoskeletal Ageeing Research

DH | National Institute for Health Research Nottingham Biomedical Research Centre

Umm Al-Qura University

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

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