Muscle fibre type switch in congenital myopathies: is it detrimental or beneficial?
PHD PROJECT DESCRIPTION
By affecting more than 25 million people in Europe, rare diseases represent an important public health issue. Unfortunately, just a few of these conditions are well enough understood to be treated effectively; and the effort to tackle them is hampered due to the complex phenotypes and low number of specialized research groups. The present research proposal focuses on one of these rare conditions, congenital myopathies (CM). The overall prevalence of CM is 1:26,000. It is rather under-appreciated in comparison with Duchenne muscular dystrophy or spinal muscular atrophy.
CM are characterised by mutations in genes encoding for sarcomeric proteins. Patients usually lose their independency and have shortened life expectancies as they experience life-threatening weakness, which affects limb, masticatory and respiratory muscles. The related medical expenses and economic consequences are therefore enormous. There is an increasing awareness in the clinical and scientific communities concerning the importance and need of a detailed pathophysiological understanding of the weakness in this growing group of disorders. However, to date, basic and clinical research has primarily focused on identifying the causative gene mutations and on defining the clinical aspects of the disorders. Hence, no cure exists; treatment simply focuses on symptomatic management such as respiratory intervention, particularly nocturnal ventilation.
In muscle cross-sections of patients with CM, pathologists often report a type I fibre predominance. Type I muscle fibre are well known to produce less force than type II fibres. Hence, the fibre type change is likely to contribute to muscle weakness. However, it remains totally unknown why such phenomenon occurs and what are its consequences.
The general objective of the present PhD research work (3 to 4 years) is to obtain a clear mechanistic understanding of the mechanisms underlying the fibre type changes in order to increase the speed of developing an efficient therapeutic intervention. Achieving this would definitely set an example for tackling other devastating rare muscle diseases such as cardiomyopathies, which are also frequently related to mutations in genes encoding for sarcomeric proteins.
We wish to have a highly motivated person with some experience in muscle research. Applicants should have a degree in cell/molecular biology or physiology and have the motivation and willingness to work as part of a team, be well-organised with excellent oral and written communication skills.
The person will join the laboratory of Dr Julien Ochala in the Centre of Human and Aerospace Physiological Sciences, Kings College London, Guy’s Campus. https://kclpure.kcl.ac.uk/portal/julien.ochala.html.
Please contact julien.ochala(at)kcl.ac.uk for enquiries.
Lindqvist J, Levy Y, Pati-Alam A, Hardeman EC, Gregorevic P, Ochala J (2016) Modulating myosin restores muscle function in a mouse model of nemaline myopathy. Ann Neurol. In press.
Ochala J, Ravenscroft G, McNamara E, Nowak KJ, Iwamoto H. (2015) X-ray recordings reveal how a human disease-linked skeletal muscle α-actin mutation leads to contractile dysfunction. J Struct Biol. 192: 331-335.
Lindqvist J, Cheng AJ, Renaud G, Hardeman EC, Ochala J (2013). Distinct underlying mechanisms of limb and respiratory muscle fiber weaknesses in nemaline myopathy. J Neuropathol Exp Neurol 72: 472-481.