Novel Approaches to Quantify the Effect of Early Versus Delayed Ankle Fracture Fixation on Muscle Mass and Metabolic Health

Overview:

Ankle fractures are a common injury in the United Kingdom. Current National Institute for Health and Care Excellence (NICE) guidelines recommend that patients with operable ankle fractures should have early surgery (within 24 hours of injury) if possible. Despite this, often patients have an operation outside of this window after injury, and undergo non-weightbearing bed rest during this time.  

The usual postoperative regime for patients with operatively treated ankle fractures is to immobilise the ankle in a cast until the bone is healed. This results in muscle wasting of the calf and ankle joint stiffness, which may be worsened by a period of bed rest before surgery. 

It is currently unknown if delayed surgery causes a more severe decline in muscle mass, architecture and insulin resistance compared with early surgery, which is likely to impact on rehabilitation. Furthermore, methods to dynamically measure changes in muscle mass and muscle turnover are laborious and invasive. This study will apply novel approaches to measure changes in muscle mass and muscle changes in patients having surgery for ankle fracture. 

This research is important to patients sustaining an ankle fracture requiring surgery as it may lead to further evidence to improve outcomes and insight into what controls muscle wasting after ankle fracture.  

Patients between the age of 18 -60 undergoing surgery for ankle fracture will be recruited at the Queen’s Medical Centre Nottingham. They will undergo physiological measures including muscle mass measurement using ultrasound, blood and calf muscle samples and a glucose tolerance test.  

Healthy matched controls will also be recruited who will undergo lower limb casting to compare with the effect of immobilisation alone. The study will be conducted at Nottingham University Hospitals and The University of Nottingham and participants will be enrolled in the study until the day after their two-week outpatient appointment. 

Aims and Objectives:

To quantify the changes in muscle protein synthesis in patients undergoing early (<48 hours) surgery vs delayed surgery (5-12 days) for ankle fracture and compared to a healthy control group undergoing immobilisation only. We will determine the changes in: 

• Muscle protein synthesis 
• Muscle protein breakdown 
• Whole body muscle mass 
• Calf muscle thickness, volume and angle of muscle fibres 
• Whole body insulin sensitivity 
• Proteins, genes and metabolites associated with the regulation of muscle protein turnover and insulin resistance 
• Inflammatory markers 
• Patient reported outcome measures, measured using validated questionnaires 

Outputs:

• Shur, NF, Simpson, EJ, Crossland, H, Chivaka, PK, Constantin, D, Cordon, SM, Constantin-Teodosiu, D, Stephens, FB, Lobo, DN, Szewczyk, N, Narici, M, Prats, C, Macdonald, IA, Greenhaff, PL. Human adaptation to immobilization: Novel insights of impacts on glucose disposal and fuel utilization. J Cachexia Sarcopenia Muscle. 2022 Dec;13(6):2999-3013. https://doi.org/10.1002/jcsm.13075
• Shur N.F, Creedon L, Skirrow S, Atherton P.J, MacDonald I.A, Lund J, Greenhaff P.L. Age-related changes in muscle architecture and metabolism in humans: The likely contribution of physical inactivity to age-related functional decline. Ageing Research Reviews April 2021. https://doi.org/10.1016/j.arr.2021.101344 
• Narici, M, De Vito, G, Franchi, M, Paoli, A, Moro, T, Marcolin, G, Grassi, B, Baldassure, G, Zuccarelli, L, Bolo, G, Giorgio di Girolama, F, Fiotti, N, Dela, F, Greenhaff, P and Maganaris, C.  Impact of sedentarism due to the COVID-19 home confinement on neuromuscular, cardiovascular and metabolic health: Physiological and pathophysiological implications and recommendations for physical and nutritional countermeasures. European Journal of Sport Science. 2020. doi.org/10.1080/17461391.2020.1761076 
• Shur N.F, Johns D, Kluzek S, Peirce N. Physical inactivity and health inequality during coronavirus: a novel opportunity or total lockdown? BMJ Open Sport & Exercise Medicine  2020. http://dx.doi.org/10.1136/bmjsem-2020-000903  

Work Package	Early Disease and Risk Prediction: Prevent
Objective	5.1i
Lead	Natalie Shur
Investigators	Paul Greenhaff, Ben Ollivere, Brigitte Scammell, Philip Atherton and Ken Smith
Institution	University of Nottingham