Improving long-term recovery Can microRNAs predict or improve muscle health and strength?

Ageing is the biggest risk for poor outcomes due to COVID-19. For those who beat the virus, premature frailty and long-term disability may become a reality. Could a small molecule hold out promise for them?

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.

Critically ill patients are at high risk of muscle loss from immobility and illness. Loss of muscle is a risk factor for death in the ICU. Loss of muscle occurs quickly in the ICU and strongly influences success for liberation from mechanical ventilation, risk for subsequent infections, rehabilitation from illness, return to usual baseline health. Understanding the process by which muscle loss occurs is needed so appropriate treatments can be developed." – Dr Bairbre McNicholas; Galway University Hospital, Galway.

About the project

Dr Kasia Whysall, Discipline of Physiology at NUI Galway, aims to help improve long-term patient recovery by reducing muscle wasting and frailty, especially among older patients.

With a new project, her approach will investigate 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.

"Skeletal muscle is highly adaptable, it can increase in size in response to exercise but also lose mass with disuse or disease. This project builds on our work demonstrating that small molecules, microRNAs, can regulate muscle health and changes in their levels may predict muscle wasting. We will study whether microRNA levels can predict muscle health and help to design personalised therapies for long-term recovery from critical illness, such as COVID-19. We will also test microRNA molecules in an approach to help prevent diaphragm and muscle loss. The combination of COVID-19 patient data with pre-clinical models will provide basis for clinical development." – Dr Kasia Whysall, NUI Galway.

The project will seek to address the medical priority of treating ICU-related diaphragm and muscle weakness and establishing biomarkers of muscle loss and frailty in COVID-19 survivors to personalise and improve patient recovery.

It builds on existing work demonstrating that microRNAs improve muscle strength in vivo and the levels of circulating microRNAs are predictors of muscle health in critically ill patients.

Validating miroRNAs

This proposal will validate the use of microRNA mimics and inhibitors of modified microRNAs to maintain diaphragm and muscle function following mechanical ventilation. The combination of COVID-19 patient data with pre-clinical models will provide pre-clinical proof-of principle for microRNA-based interventions and biomarkers for clinical development.

The successful outcome of this project may improve patient recovery post-ICU for COVID-19, reducing pressure on the healthcare system, critical in the current pandemic and for our ageing population.

"The Covid-19 pandemic is disproportionately affecting middle aged and older adults. Despite this, few data are available on how best to manage these patients, particularly in the post-acute recovery phase. As frailty and associated sarcopenia (loss of muscle mass and strength) are likely to be important factors influencing recovery, this study will explore how these relate to muscle health and long-term recovery to help identify and develop targeted treatments for those at greatest risk. "– Dr Rónán O’Caoimh, Mercy University Hospital, Cork.

The project is funded by Ireland's national COVID-19 Rapid Response Research and Innovation funding, via the Health Research Board and Irish Research Council. #CovidResearchIreland

About the PI

Dr Kasia Whysall is an IRC Laureate and Senior Lecturer at NUI Galway & University of Liverpool.

During her PhD at the University of East Anglia she studied the role of microRNAs in skeletal muscle development.

This has led to a discovery of microRNA-based mechanisms controlling Pax3 expression during embryonic development of skeletal muscle. She continued her research at the University of East Anglia and characterised novel microRNA:chromatin regulators interactions during muscle development. In 2013, she moved to Institute of Ageing and Chronic Disease, Liverpool and has been studying the role of epigenetic changes in sarcopenia and osteoarthritis development.

Dr Whysall's research has shown the critical role of microRNA in regulation of muscle mass and function during ageing. In Galway, her focus is on the therapeutic potential of microRNAs against muscle loss during ageing and disease, such as cachexia and ALS.