Project: The complex mechanisms behind resistance to stretch of active muscle
Stretch of active muscle is of great significance for the evolutionary optimized function of our muscle but the mechanisms as a basis for high resistance to stretch of the muscle is poorly understood. The present project elucidates these mechanisms by studies of isolated muscle proteins.
Facts about the project
Project manager Alf Månsson Other project members Marko Usaj och Luisa Moretto, Linnéuniversitetet; Heiner Linke, Lunds Universitet; Dilson E Rassier, McGill University, Montreal. Participating organizations Linnaeus University, Lunds University, McGill University Financier Swedish Research Council VR (The Swedish Research Council Open Calls 2019) Timetable 1 jan 2020 -31 dec 2024 Subject Biomedicine (Department of Chemistry and Biomedical Sciences, Faculty of Health and Life Sciences) Research group The Molecular motor and bionano-group
More about the project
Striated muscle (heart and skeletal muscle) are evolutionary optimized machines that use the proteins actin and myosin II to develop force and motion. Stretch of active muscle (“eccentric contraction”) is a critical facet of normal function with potential importance in muscle diseases. Despite the significance, the molecular mechanisms are considerably less well understood than in active muscle-shortening.
We here propose to investigate these issues in mammalian muscle with focus on actin and myosin. To this end we will use newly developed techniques (year 1) for unique tests of hypotheses about:
dominant roles of actin and myosin compared to e.g. titin (year 1-2),
roles of the two myosin motor domains (years 2-4) and finally
myosin slippage between actin sites (years 2-4) The novel experimental systems combine:
a) recording of force developed by a myosin ensemble on actin upon imposition of sub-micrometer length changes,
b) an enhanced method for recording ATP turnover by single motors and
c) expression of mammalian myosin in C 2C 12 cells for genetically engineered motors.
The experiments will be aided by computational modelling and control experiments on higher level of hierarchical order such as myofibrils. The new set of miniaturized experimental methods will be of general value also for studies on other systems. We expect new levels of insight into eccentric contraction mechanisms, of value for drug development, understanding of pathologies and other fields.
Image from the RCSB PDB (rcsb.org) of PDB ID 2OTG (Yang, Y., Gourinath, S., Kovacs, M., Nyitray, L., Reutzel, R., Himmel, D.M., O'Neall-Hennessey, E., Reshetnikova, L., Szent-Gyorgyi, A.G., Brown, J.H., Cohen, C. (2007) Rigor-like Structures from Muscle Myosins Reveal Key Mechanical Elements in the Transduction Pathways of This Allosteric Motor.