Welcome to our research group studying the role of RNAs in muscle ageing and disease
fit-miRs as potential therapeutics for muscle wasting
Irreversible muscle loss and weakness are a growing issue of our ageing population with substantial socio-economic burden on European health services that will increase without the development of effective therapies. There are currently no treatments to target muscle loss despite the significant health and social issues associated with it.
Sarcopenia (age-related muscle loss), amyotrophic lateral sclerosis (a progressive disease associated with motor neuron degeneration and muscle loss) and cachexia (a progressive wasting syndrome) are multifactorial conditions, sharing several common mechanisms associated with muscle wasting, hospitalisation and decreased lifespan. microRNAs (miRNAs), potent regulators of gene expression, provide an attractive alternative strategy against muscle loss due to their simultaneous regulation of multiple gene expression without safety issues.
Using state-of-the-art omics approaches and discovery-driven bioinformatic tools, we will establish a set of conserved key miRNAs, fit-miRs, commonly dysregulated in muscle in ageing and disease. Functional studies in complementary models of in vitro and in vivo muscle loss will validate the crucial role of fit-miRs in muscle homeostasis and their potential to improve muscle mass and strength in ageing and disease.
microRNA oxidation in health and disease
Loss of skeletal muscle mass and strength with age is one of the primary underlying causes of hospitalisation and bed rest. Currently there is no effective treatment although resistance exercise has proved to delay its onset. Understanding the underlying cellular changes is essential for designing an effective therapy. Key regulatory molecules that control the level of expression of proteins within the muscle are called microRNAs. However, these molecules can be targeted by other molecules generated within the cell such as ROS. Modification of microRNAs can result in a loss of specificity for their targets and pathogenesis. A vicious cycle occurs during ageing with a dysregulation of miRNAs, resulting in aberrant protein regulation and muscle wasting.
Improving long-term recovery following critical illness such as COVID-19
Approximately 58% of those hospitalised in Ireland are aged >65 and many require ICU. Ventilator-induced diaphragm dysfunction (VIDD) and muscle wasting are found in critically ill patients within 24 hours of initiation of mechanical ventilation and can persist beyond 12 months.
Elevated cytokine levels, immunosenescence and muscle weakness are common in older people. COVID-19 patients with severe ARDS show increased IL6 levels and macrophage activation and are often administered drugs inducing muscle relaxation during ventilation, further increasing risk of muscle wasting in survivors.
Therefore, COVID-19 critical illness, especially in older people, is likely to lead to premature frailty and long-term disability, loss of independence, further hospitalisation and increased morbidity and mortality. There is no effective treatment for muscle wasting. Muscle loss leading to frailty is an increasing socio-economic and healthcare challenge in our ageing population and is likely to become a public health priority in the light of the current pandemic.
In this HRB-funded project, we are investigating whether microRNAs, small molecules which regulate the function of our cells, can predict or improve muscle health and strength following critical illness such as COVID-19.
The project is a collaboration with NUI Galway’s Dr Brian McDonagh and Professor John Laffey, Dr Bairbre McNicholas of University Hospital Galway, Professor Ken O'Halloran from UCC and Dr Rónán O’Caoimh from Mercy University Hospital Cork.
siRNAs and ASOs as personalised therapeutics for ultra-rare conditions
It is estimated that one in 17 people will suffer from a rare disorder during their lifetime. Rare genetic neuromuscular disorders (NMDs) are increasingly being discovered. These are often severe and life-limiting, with no effective treatments for most. Underlying this unmet clinical need are the lack of knowledge in precise pathophysiology associated with new mutations and their rarity, resulting in patient prognosis being unknown. Gene editing (CRISPR) and RNA technologies are emerging as promising therapeutic tools following limited success of stem cell therapies in clinical trials for NMDs. The enormous success of Nusinersen (Spinraza), the first approved RNA therapy for a rare genetic NMD: spinal muscular atrophy associated with degenerative changes in central and peripheral nervous system and muscle, and worldwide success of RNA vaccines, provide undisputable evidence of the therapeutic potential of RNA modalities. Moreover, RNA therapeutics can be tailored for patient-specific therapies through custom sequences.
We are developing rapid screening system of functional consequences of novel mutations associated with NMDs affecting central and peripheral nervous system and muscle, for the design of personalised therapies.
microRNAs role in Osteoarthritis
Musculoskeletal system disorders are among the five most prevalent conditions affecting older people. Osteoarthritis (OA) is a subset of joint disorders with various aetiologies (eg. mechanical, genetic) sharing common pathophysiological processes resulting in degeneration of synovial joints. This leads to pain, disability and loss of independence. Similarly, muscle wasting directly affects the stability of the joints and loss of mobility leads to gradual degeneration of articular cartilage (AC).
Progressive loss of muscle has consequences on joint stability and health. Muscle wasting is associated with OA. Over the past few years, the relationship between cartilage and the surrounding skeletal muscle has become more evident. Already during embryogenesis, muscle contractility is required for joint formation and during OA, muscle weakness has been shown to be an important determinant of pain and disability. Several studies have shown that a decrease in lower limb lean mass is frequent in OA patients and this is associated with greater risk of falls. Moreover, it has been shown that muscle damage was associated with articular cartilage degeneration, whereas increased cross sectional area of vastus medialis was associated with improved structural changes at the knee and reduced pain in OA patients.
We propose that muscle wasting is an important component of OA pathology and by improving muscle mass and function the symptoms of OA can be ameliorated. This project is a collaboration with Prof. G. Bou-gharios, Dr. B. Poulet, Dr. M. Peffers and Prof. P. Clegg, University of Liverpool, UK
microRNA regulation of cell senescence
Muscle wasting with age and chronic disease, for which there is no cure. Muscle homeostasis is a balance between muscle hypertrophy and atrophy and regeneration. Changes in satellite cell, adult muscle stem cells, number and function have been demonstrated during ageing and disease. We are investigating the role of cell senescence in cell population within muscle in sarcopenia development.
The effects of maternal diet on neuromuscular homeostasis in offspring
This project is a collaboration with Dr. Aphrodite Vasilaki and Prof. Susan Ozanne and it aims to establish whether changes in maternal diet can affect premature muscle wasting in the offspring. We are also trying to establish whether such changes could be regulated by microRNAs.