Determining how mutations in actin lead to skeletal muscle weakness

Lead Research Organisation: King's College London
Department Name: Ctr of Human & Aerospace Physiolog Sci


Skeletal muscles are composed of a large number of cells called myofibres. Each myofibre have myofibrils consisting of sarcomeres in series and parallel. Each sarcomere is formed by overlapping arrays of thick filaments and thin filaments also known as myosin and actin filaments. Myosin and actin filaments represent the contractile machinery.

There are many acquired and inherited diseases affecting myosin and actin filaments. Among them, actinopathies are the most common and are caused by mutations in actin. Actinopathies are usually life threatening, as they are associated with severe weakness affecting limbs and respiratory muscles. How mutations in actin lead to muscle weakness remains obscure and will be addressed in the present research project. Deciphering this will undoubtedly help designing efficient therapeutic interventions.

Technical Summary

Importance and main objective: Diseases related to mutations in actin are characterized by severe skeletal muscle weakness often leading to premature death. The understanding of this group of disorders has advanced in recent years through the identification of the causative ACTA1 gene mutations. Nevertheless, the exact mechanisms leading to muscle dysfunction remain unclear, which hampers the development of efficient therapies. Therefore, the main objective of the present research project is to clearly characterise the cascade of molecular and cellular events triggering muscle wasting.

Methods: We will mainly use muscle samples and isolated myofibres from two transgenic mouse models perfectly recapitulating the human condition and expressing either His40Tyr or Asp286Gly single amino acid substitution in actin. We will then perform a broad range of experiments including small-angle X-ray scattering, polarised fluorescence, myofibre mechanics, confocal microscopy, immunohistochemistry and micro-array analysis.

Feasibility and outcomes: The availability and knowledge of these unique techniques in combination with experience in undertaking challenging studies put us in a unique position to tackle the problem posed. We expect to demonstrate that mutations in actin directly impair actin filament extensibility, inducing a disruption (i) of myosin binding and (ii) of the intrinsic force-generating capacity, directly promoting myofibre atrophy. Successfully proving this would grandly facilitate the design of efficient therapeutic interventions that would target the actin-myosin interface.

Planned Impact

1. Impact by training:
As with any reputable scientific centre we are concerned that young scientists who come for training should be given as wide a scope as possible in order to keep their future scientific options open. This project will allow the development of the appointed individual to develop a range of unique and specialist skills such as:
(i) Learning new techniques; and
(ii) Gaining communication skills by presenting his/ her work to the scientific and medical communities and to a more general audience.

2. Impact on basic research and academia:
The effort to tackle rare diseases is hampered due to the complex phenotypes and low number of specialized research groups. The present research project combining state-of-the-art methods and unique techniques has the potential to move the field into completely uncharted scientific territory. We predict that the findings of the present proposal, at the interface between physiology and biophysics, will be of great interest for:
(i) Geneticists who focus on gene mutations and their consequences;
(ii) Structural and cell/ molecular biologists, who are interested in actin structure and function;
(iii) Biophysicists who use similar techniques including small-angle x-ray scattering;
(iv) Physiologists who investigate skeletal/ cardiac muscle structure and function in health and disease; and
(v) Clinicians who try to understand the pathophysiology of muscle diseases.

3. Impact on the clinic:
Rare diseases affect more than 25 million people in Europe. Only a few of these disorders are well enough understood to be treated effectively. Thus, rare diseases are still an important public health challenge. Our research project has the potential to contribute to the nation's health by
(i) Generating attention from affected patients, family members, general practitioners, myologists, neurologists, pathologists and physiotherapists; and
(ii) Setting an example for tackling other rare (muscle) diseases such as cardiomyopathies, which are also frequently related to mutations in genes encoding actin.

4. Impact on pharmaceutical industry:
Actinopathies start at a very young age. Hence, the economic consequences are large (loss of ability to work, large medical expenses) and the impact on family members is enormous, as they need to take care of the affected patients as long as they live. The fact that we will unravel the pathophysiological mechanisms underlying weakness in a group of rare disorders termed actinopathies will:
(i) Provide a clear understanding of how mutations in actin cause disease; and
(ii) Give opportunities for industrial applications; in other words, help to increase the speed of developing therapeutic interventions by identifying potential drug targets.

5. Impact on society via engagement of the public in science:
The PI of this application is a member of various scientific societies and takes active roles in trying to engage interested members of the public, particularly younger people, in science. The Centre of Human and Aerospace Physiological Sciences has an outstanding track record in linking its research to public engagement and activities for engaging young people. This includes endeavours such as "Mission Discovery", a weeklong summer school using the physiology of human space flight to facilitate and engage children in biomedical science and designing experiments, which run on the International Space Station:


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Jungbluth H (2017) Current and future therapeutic approaches to the congenital myopathies. in Seminars in cell & developmental biology

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Ross JA (2018) SIRT1 regulates nuclear number and domain size in skeletal muscle fibers. in Journal of cellular physiology

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Buono S (2018) Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy. in Proceedings of the National Academy of Sciences of the United States of America

Description Research grant
Amount $135,000 (USD)
Organisation A Foundation Building Strength for Nemaline Myopathy 
Sector Charity/Non Profit
Country United States
Start 05/2018 
End 01/2020
Description Research grant
Amount £112,535 (GBP)
Funding ID 17GRO-PS48-0077 
Organisation Muscular Dystrophy UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 12/2021
Description Nemaline Myopathy 
Organisation University of Western Australia
Department Western Australian Institute for Medical Research
Country Australia 
Sector Academic/University 
PI Contribution We are studying how muscle physiology is changed in these mouse models
Collaborator Contribution They are providing muscle tissue from various mouse models
Impact We have published a few scientific papers and a couple more are currently written
Start Year 2017
Description Outreach/fundraising event for Muscular Dystrophy UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact It is an event to raise awareness and funds for the charity titled Muscular Dystrophy UK. I will talk about why it is important to fund research related to muscle diseases and what my research is about.
Year(s) Of Engagement Activity 2018
Description Webinar (A Foundation Building Strength for Nemaline Myopathy) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact I take active roles in trying to engage members of the public, particularly patients and their relatives. In fact, in 2016 and 2017, I have given two webinars aiming at informing patients and their families about the latest research advances in the field of genetic diseases and congenital myopathies (organised by the "Foundation Building Strength for Nemaline Myopathy").
Year(s) Of Engagement Activity 2016,2017
Description Webinar about Genetic Muscle Diseases for the Asociaci√≥n Conquistando Escalones 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact 20 patients diagnosed with genetic muscle diseases (LGMD) attended the webinar where I presented my recent work on the mechanisms underlying congenital myopathies and dystrophies.
Year(s) Of Engagement Activity 2018