Role of myonectin in the regulation of the lipid metabolism in the metabolic syndrome

ABSTRACT: Metabolic syndrome (MS) encompasses conditions including hypertension, central obesity, glycemic dysfunctions, and atherogenic dyslipidemia, affecting ~40% of adults in Colombia and worldwide. This condition increases mortality from all causes. Myokines, molecules secreted by the skeletal...

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Autores:: Petro Soto, Jorge Luis

Tipo de recurso:: Doctoral thesis

Fecha de publicación:: 2024

Institución:: Universidad de Antioquia

Repositorio:: Repositorio UdeA

Idioma:: eng

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Summary:	ABSTRACT: Metabolic syndrome (MS) encompasses conditions including hypertension, central obesity, glycemic dysfunctions, and atherogenic dyslipidemia, affecting ~40% of adults in Colombia and worldwide. This condition increases mortality from all causes. Myokines, molecules secreted by the skeletal muscle with autocrine, paracrine, and endocrine actions, emerge as key players in the pathophysiology of the MS, modulating the metabolism of tissues such as muscle, adipose, and liver. Myonectin is a myokine which has shown significant effects on lipid regulation, including reducing free fatty acids (FFA) in serum in murine models and increasing the uptake of these substrates in adipocytes, through the upregulation of fatty acid transporters (e.g., Cd36 and Fabp4). Additionally, myonectin increases the expression of molecular markers related to metabolism and mitochondrial biogenesis in adipocytes and skeletal muscle (e.g., Tfam, Nrf1). However, there is no evidence about the effect of myonectin on the mitochondrial function in the living skeletal muscle cell, despite the key role of this tissue in the pathophysiology of the MS. Also, human studies have not agreed with basic sciences data and have yielded contradictory results; some show a positive correlation of myonectin with MS outcomes, while others indicate a negative correlation. Considering this context, the purpose of this study was to evaluate the role of myonectin in lipid metabolism regulation at various complexity levels (i.e., body, serum, tissue, and cell) to deepen our understanding of its role in the pathophysiology of the MS. This research implemented two study models: one in humans at metabolic risk, defined by the presence of at least one MS component of both sexes, aged between 40 and 60 years, and another in murine skeletal muscle cells. The human model included a secondary analysis of databases and samples from the Intraining-MET study (NCT03087721), addressing a cross- sectional design and a randomized controlled trial (RCT). In this model, serum myonectin was quantified by enzyme-linked immunosorbent assay, lipid profile by conventional techniques, FFA by gas chromatography, body composition assessed by dual-energy X-ray absorptiometry, and intramuscular lipid content by proton nuclear magnetic resonance spectroscopy in the right vastus lateralis muscle. The cross-sectional study considered participants at metabolic risk but without MS (with between 1 and less than 3 MS components, n = 29) and with MS (≥3 MS components and insulin resistance, n = 61). In the RCT, subjects with MS (n = 60) were assigned to either high-intensity interval training (HIIT, n = 29) or moderate-intensity continuous training (MICT, n = 31) for 12 weeks. The cellular model focused on assessing mitochondrial function in C2C12 myoblasts and isolated muscle fibers of mice. This analysis included measuring the oxygen consumption rate (OCR) via extracellular flux assays, mitochondrial membrane potential (Δψm), and levels of reactive oxygen species (particularly superoxide) in C2C12 myoblasts using flow cytometry. The results from the human cross-sectional study indicated that serum myonectin levels were lower in participants with MS and showed a negative correlation with central obesity in individuals with metabolic risk factors, after multiple adjustments (R2=0.477, p<0.001), suggesting that low concentrations of this myokine may be linked to a higher abdominal fat accumulation. In the RCT, HIIT did not prove superior in improving serum lipid markers compared to MICT, although it increased myonectin significatively (p=0.042), with a large effect size, when compared to baseline values. Also, both interventions reduced fat mass (FM) after 12 weeks without parallel changes in serum myonectin levels, which could indicate a limited effect of this myokine on exercise-induced fat mobilization in the medium term. Moreover, the myonectin treatment of murine, healthy or metabolically altered C2C12 muscle cells, and mature, isolated fibers from healthy or obese mice, induced an increase in OCR and adenosine triphosphate (ATP) production linked to oxidative phosphorylation in control muscle fibers, with no significant changes in Δψm or superoxide production levels. We conclude that low myonectin concentrations in individuals with MS may be linked to increased abdominal fat accumulation, which contributes to the pathophysiology of this syndrome. This myokine appears to have a minor effect on the serum lipid outcomes and intramuscular fat content. Only HIIT increased myonectin in serum. Our evidence suggests a low mediating effect of this myokine on lipid outcomes during exercise. On the other hand, findings in cellular models indicate that myonectin promotes a healthy metabolic phenotype, although it is not sufficient to completely reverse the effects of a severe or chronic condition of lipid alteration. Studies in cellular models are more convincing of a measurable and beneficial effect of myonectin on the metabolism, than studies in humans. Given that myonectin seems to be a low, and slow, responding myokine, its study in humans likely requires larger samples and longer times of observation. As a claim of novelty, this Thesis is the first to show: i) an inverse correlation of myonectin with android obesity in subjects with MS, after multiple adjustments; ii) the lack of correlation of myonectin with myosteatosis in humans; iii) an increase in myonectin after a HIIT intervention in humans; iv) an increase in OCR and ATP production linked to oxidative phosphorylation in muscle fibers incubated with myonectin. All these findings increase our knowledge about the role of myonectin in the regulation of the lipid metabolism and the pathophysiology of the MS.

Role of myonectin in the regulation of the lipid metabolism in the metabolic syndrome

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