Musculoskeletal tissues ageing: the role of microRNAs and joints homeostasis
Lead Research Organisation:
University of Liverpool
Department Name: Institute of Ageing and Chronic Disease
Abstract
The societal impact of musculoskeletal (MSK) disorders is increasing as the number of older people is predicted to reach over 60 million (in UK) by 2020. It is therefore essential to determine the mechanisms underlying age-related functional deterioration of MSK tissues. It is likely that deterioration of the individual MSK tissue may depend on the state of the other MSK tissues, eg joint degeneration may be affected by muscle weakness. The molecular mechanisms governing MSK ageing are still not understood, however epigenetic mechanisms are thought to play key roles.
microRNAs (miRs), robust regulators of gene expression, affect the functionality of most tissues and provide a high-throughput response mechanism to ageing and environmental changes (Brown & Goljanek-Whysall, 2015). Differential expression of miRs in muscle, bone and cartilage has been described during ageing, however the relevance of this is not fully understood (Soriano, 2016; Steinbush, 2017).
Our data shows changes in the expression of several miRs: miR-24, miR-128 and miR-34, and their targets in MSK tissues of old mice. These miRs have been shown or are predicted to target fundamental genes for MSK tissue homeostasis: extracellular matrix genes and TGFB signalling. We have also shown that regulation of miR expression improves muscle mass and strength in old mice (man in prep). Although limited, our data indicates the involvement of miRs in driving osteoarthritis-like changes during ageing. Specifically, we have shown that miR-199 dysregulation in cartilage of old mice are associated with cartilage degeneration; this can be modulated using intraarticular injections of miR-199 mimic/antagomiR in the loading model of osteoarthritis (Poulet, 2011).
The overall aim of this project is to establish whether disrupted miR:target interactions affect MSK tissue ageing and whether miR-based intervention has the potential to ameliorate age-related MSK dysfunction associated with muscle wasting and OA-like symptoms. Specifically, we will:
1. Validate expression of selected miRs and their predicted targets in skeletal muscle, cartilage, bone during ageing.
2. Investigate miR:target regulatory network(s) in vitro and in vivo using established miR gain- and loss-of-function approaches and target gene reporters.
3. Establish the effects of interventions in vitro and in vivo on miR:target interactions on musculoskeletal tissue homeostasis during ageing.
microRNAs (miRs), robust regulators of gene expression, affect the functionality of most tissues and provide a high-throughput response mechanism to ageing and environmental changes (Brown & Goljanek-Whysall, 2015). Differential expression of miRs in muscle, bone and cartilage has been described during ageing, however the relevance of this is not fully understood (Soriano, 2016; Steinbush, 2017).
Our data shows changes in the expression of several miRs: miR-24, miR-128 and miR-34, and their targets in MSK tissues of old mice. These miRs have been shown or are predicted to target fundamental genes for MSK tissue homeostasis: extracellular matrix genes and TGFB signalling. We have also shown that regulation of miR expression improves muscle mass and strength in old mice (man in prep). Although limited, our data indicates the involvement of miRs in driving osteoarthritis-like changes during ageing. Specifically, we have shown that miR-199 dysregulation in cartilage of old mice are associated with cartilage degeneration; this can be modulated using intraarticular injections of miR-199 mimic/antagomiR in the loading model of osteoarthritis (Poulet, 2011).
The overall aim of this project is to establish whether disrupted miR:target interactions affect MSK tissue ageing and whether miR-based intervention has the potential to ameliorate age-related MSK dysfunction associated with muscle wasting and OA-like symptoms. Specifically, we will:
1. Validate expression of selected miRs and their predicted targets in skeletal muscle, cartilage, bone during ageing.
2. Investigate miR:target regulatory network(s) in vitro and in vivo using established miR gain- and loss-of-function approaches and target gene reporters.
3. Establish the effects of interventions in vitro and in vivo on miR:target interactions on musculoskeletal tissue homeostasis during ageing.
