Abstract

The role of microRNAs in metabolic diseases has been recognized and modulation of them could be a promising strategy to treat obesity and obesity-related diseases. The major purpose of this study was to test the hypothesis that intramuscular miR-1 precursor replacement therapy could improve metabolic parameters of mice fed a high-fat diet. To this end, we first injected miR-1 precursor intramuscularly in high-fat diet-fed mice and evaluated glucose tolerance, insulin sensitivity, and adiposity. miR-1-treated mice did not lose weight but had improved insulin sensitivity measured by insulin tolerance test. Next, using an in vitro model of insulin resistance by treating C2C12 cells with palmitic acid (PA), we overexpressed miR-1 and measured p-Akt content and the transcription levels of a protein related to fatty acid oxidation. We found that miR-1 could not restore insulin sensitivity in C2C12 cells, as indicated by p-Akt levels and that miR-1 increased expression of Pgc1a and Cpt1b in PA-treated cells, suggesting a possible role of miR-1 in mitochondrial respiration. Finally, we analyzed mitochondrial oxygen consumption in primary skeletal muscle cells treated with PA and transfected with or without miR-1 mimic. PA-treated cells showed reduced basal respiration, oxygen consumption rate-linked ATP production, maximal and spare capacity, and miR-1 overexpression could prevent impairments in mitochondrial respiration. Our data suggest a role of miR-1 in systemic insulin sensitivity and a new function of miR-1 in regulating mitochondrial respiration in skeletal muscle.

Highlights

  • Obesity, an abnormal or excessive fat accumulation that presents a risk to health, is strongly associated with type 2 diabetes mellitus (T2DM) (Boles et al, 2017)

  • MiR-1 is a well-known myomiR that is crucial for myotube differentiation, which is dysregulated in the skeletal muscle of obese and diabetic individuals (Chen et al, 2012; Frias et al, 2016, 2018; Dahlmans et al, 2017)

  • MiR-1 may have a role in mitochondrial function in the skeletal muscle of obese subjects and intramuscular miR1 precursor replacement therapy improves peripheral insulin resistance in obese mice

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Summary

Introduction

An abnormal or excessive fat accumulation that presents a risk to health, is strongly associated with type 2 diabetes mellitus (T2DM) (Boles et al, 2017). Intramyocellular lipid accumulation, resulting from enhanced adipose tissue lipolysis and impaired fatty acid beta-oxidation in skeletal muscle, induces insulin resistance, a major defect involved in the development of T2DM (Sergi et al, 2019). Mitochondrial reduced function in muscle has been associated with this metabolic inflexibility observed in T2DM patients. Enhancing mitochondrial function in skeletal muscle may be a strategy to improve insulin sensitivity. MicroRNAs (miRNA or miR), small non-coding RNAs that negatively regulate gene expression, are increasingly being characterized as important regulators of mitochondrial function in obesity (Murri and El Azzouzi, 2018). As acknowledged by Bandiera et al (2013), miRNA can be found in mitochondria acting within the organelle, while nuclear-encoded miRNAs can act at mitochondria or in the nucleus/cytosol on genes encoding mitochondrial proteins

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