Ana Soriano-Arroquia

Small extracellular vesicles (small EVs) are nanovesicles found in tissues and body fluids that contain regulatory molecules including microRNAs, termed exomiRs. Research in murine models has demonstrated that exercise can trigger the release of small EVs into the circulation. The aim of this study was to study exomiR release in humans pre and post exercise and to characterise the function of these microRNAs especially in relation to thermogenic fat. We found that exercise increased the release of exomiR-196a-5p in endurance athletes, a microRNA that induces UCP1 expression and browning of white adipocytes. We observed that myotubes specifically release miR-196a-5p within small EVs after in vitro exercise-mimicking conditions such as electrical pulse stimulation and cAMP treatment. Likewise, the expression at basal levels of the exercise-induced exomiR-342-3p negatively correlated with BMI and age. EV proteomics revealed a positive correlation between FABP4+ and miR-342-3p, suggesting an adipocyte cell origin. Overexpression of miR-342-3p increased Myogenin levels during skeletal muscle cell differentiation, indicating a positive role in muscle differentiation. Our results suggest that oxidative extreme metabolic capacities in endurance athletes contribute to the enhanced release of circulatory exomiRs after exercise mediating bi-directional crosstalk between skeletal muscle and thermogenic adipose tissue. Graphical Serum-EVs from endurance athletes increase UCP1 expression in white adipocytes. miR-196a and miR-342-3p are increased in serum-EVs from endurance athletes. Muscle cells release EVs enriched in miR-196a after electrical pulse stimulation. miR-196a and miR-342-3p have browning and myogenic potential, respectively.

Brown and beige adipose tissue activate non-shivering thermogenesis in response to cold exposure or beta-adrenergic agonists. During this process, glucose and lipids are used to generate heat through mitochondrial uncoupling, increasing energy expenditure at the expense of adenosine triphosphate (ATP) production. Importantly, the decline in brown adipose tissue negatively correlates with age and body mass index (BMI). This is, therefore, why induced “browning” of white adipose tissue is proposed as a promising therapeutic approach against obesity and metabolic diseases. In this chapter, we will review the intricate and exciting world of non-shivering thermogenesis, from the molecular mechanisms to the potential pharmacological treatments that are currently under scientific scrutiny, as well as the role that batokines, BAT-derived adipokines, play in inter-tissue crosstalk after certain stimuli such as cold exposure and exercise.

Aim: Osteoporosis (OP) is caused by imbalanced bone remodelling homeostasis. It is highly prevalent, especially in post-menopausal women, resulting in high risk of fracture and morbidity. Mesenchymal stromal cells (MSCs) are osteoblast progenitors, and orchestrate the function of surrounding cells including osteoblasts. Understanding MSC phenotype and function is therefore critical in discerning the aetiology of OP and developing superior therapies. Currently, adequate long-term therapeutic strategies are not available. Methods: Bioinformatic analysis of ribonucleic acid sequencing (RNA-seq) data revealed differential expression of genes primarily related to osteogenic differentiation and proliferation, followed by confirmatory in vitro analysis. Results: This study identified novel and previously proposed targets for therapeutic intervention in OP. Functional assessment demonstrated reduced MSC number and osteogenic capacity associated with OP. Proliferation was not affected but OP was unexpectedly associated with a reduction in MSC adipogenic differentiation capacity, correlating with donor age. Conclusions: These data indicate specific targets for further studies of future treatments for OP, including the assessment of modified MSCs as therapeutics. Advances in this area may contribute to reducing fracture-associated morbidity and mortality, and improving quality of life for the 200 million people living with OP globally.

One of the key mechanisms underlying skeletal muscle functional deterioration during ageing is disrupted mitochondrial dynamics. Regulation of mitochondrial dynamics is essential to maintain a healthy mitochondrial population and prevent the accumulation of damaged mitochondria, however the regulatory mechanisms are poorly understood. We demonstrated loss of mitochondrial content and disrupted mitochondrial dynamics in muscle during ageing concomitant with dysregulation of miR-181a target interactions. Using functional approaches and mitoQc assay, we have established that miR-181a is an endogenous regulator of mitochondrial dynamics through concerted regulation of Park2, p62/SQSTM1 and DJ-1 in vitro . Downregulation of miR-181a with age was associated with an accumulation of autophagy-related proteins and abnormal mitochondria. Restoring miR-181a levels in old mice prevented accumulation of p62, DJ-1 and PARK2, improved mitochondrial quality and muscle function. These results provide physiological evidence for the potential of microRNA-based interventions for age-related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.