Nutrition and microRNAs: Novel Insights to Fight Sarcopenia

Abstract

Sarcopenia is a progressive age-related loss of skeletal muscle mass and strength, which may result in increased physical frailty and a higher risk of adverse events. Low-grade systemic inflammation, loss of muscle protein homeostasis, mitochondrial dysfunction, and reduced number and function of satellite cells seem to be the key points for the induction of muscle wasting, contributing to the pathophysiological mechanisms of sarcopenia. While a range of genetic, hormonal, and environmental factors has been reported to contribute to the onset of sarcopenia, dietary interventions targeting protein or antioxidant intake may have a positive effect in increasing muscle mass and strength, regulating protein homeostasis, oxidative reaction, and cell autophagy, thus providing a cellular lifespan extension. MicroRNAs (miRNAs) are endogenous small non-coding RNAs, which control gene expression in different tissues. In skeletal muscle, a range of miRNAs, named myomiRNAs, are involved in many physiological processes, such as growth, development, and maintenance of muscle mass and function. This review aims to present and to discuss some of the most relevant molecular mechanisms related to the pathophysiological effect of sarcopenia. Besides, we explored the role of nutrition as a possible way to counteract the loss of muscle mass and function associated with ageing, with special attention paid to nutrient-dependent miRNAs regulation. This review will provide important information to better understand sarcopenia and, thus, to facilitate research and therapeutic strategies to counteract the pathophysiological effect of ageing.

Keywords: TNF; ageing; autophagy; fructose; hormesis; inflammation; nutrition; oxidative stress; skeletal muscle; uric acid; vitagene.

Figure 1

Schematic representation of cellular processes involved in the onset of sarcopenia during ageing. During ageing multifactorial events such as protein synthesis/degradation imbalance, satellite cell number/activity impairment, chronic inflammation, mitochondrial dysfunction, and fat infiltration increase contributing to the onset of sarcopenia.

Figure 2

Schematic representation of nutrient-dependent-miRNA signaling in skeletal myogenesis. Nutrients such as essential amino acids (EAAs) may affect the expression of miR-133a/b and miR-206 through mTOR-dependent regulation of MyoD mRNA levels. On the other hand, EAAs may elicit robust increases in miR-1, miR-23a, miR-208b, and miR-499 expression, with an accompanying increase in MyoD and follistatin mRNA and decrease in myostatin and MEF2C mRNA expression, regulating skeletal muscle growth and differentiation.

Figure 3

Schematic representation of fructose metabolism and uric acid effect on skeletal muscle. In the liver, fructose is phosphorylated into fructose 1-phosphate by fructokinase in a reaction that decreases the levels of intracellular phosphate and ATP. Subsequently, the enzyme fructose-1-phosphate aldolase gives rise to dihydroxyacetone phosphate (DHAP) and glyceraldehyde. When fructose 1-phosphate accumulates, intracellular phosphate decreases, stimulating AMP deaminase, which catalyzes the degradation of AMP to inosine monophosphate (IMP). IMP is metabolized to inosine, which is further degraded to xanthine and hypoxanthine by xanthine oxidase, ultimately generating uric acid (UA). UA can induce ROS production in the liver and other tissues, such as skeletal muscle via TGFβ-1-NOX4 signaling. Alternatively, fructose can stimulate de novo lipogenesis in the liver with increased release of lipids and lipoproteins in the bloodstream that are then uptaken by different tissues including skeletal muscle, with consequent cytokines and ROS production. Besides, high levels of fructose can modulate the expression of miRNAs that may affect skeletal muscle cell proliferation, differentiation, and insulin signaling.