The process of aging is associated with a progressive decline in many physiological functions, impacting quality of life for elderly individuals. Within muscles, the loss of mass and function with age is termed sarcopenia, and represents a major public health problem with enormous clinical and societal consequences. The cellular mechanisms underlying sarcopenia and aging remain unclear, and this lack of understanding has impaired our ability to develop treatments.
Aggregated proteins have been almost universally observed in aging tissues in many species, though whether they are an epiphenomenon of aging or contribute directly to cellular and functional impairment is unknown. Insight from genetic diseases such as myofibrillar myopathies (MFM) in which an excess of muscle protein aggregates develop alongside progressive muscle wasting suggest that protein aggregates, at least in muscle, may directly contribute to aging and sarcopenia. If true, then reducing protein accumulation within muscles may represent a novel treatment paradigm for sarcopenia.
Secondly, work within the central nervous system has shown that such aggregated proteins do not always accumulate independently within cells. Some proteins spread from cell-to-cell in a prion-like or ‘metastatic’ fashion particularly in neurons, as observed in diseases such as Alzheimer’s disease and Parkinson’s disease. If this were also the case in aging muscle it would transform the way we understand the process of muscle aging and alter our approach to treatment.
In this project, you will have the opportunity to use cutting-edge techniques such as mass spectrometry, imaging mass cytometry and nuclear magnetic resonance fibrillisation assays to identify and quantify protein aggregates in post-mortem aged human muscle tissues and from individuals with protein aggregation disorders (MFM) to understand and quantify protein aggregate formation. Thereafter, you will study how aggregates affect cell stiffness and elucidate their impact on nuclear structure, composition, motility, and positioning which are fundamental for the fitness and mechano-responsiveness of muscle cells. Finally, you will build novel 3D cell culture models to determine whether and how human muscle can develop and transmit identified proteins between them. To achieve this you will work across three internationally recognised laboratories who study muscle diseases, aging and protein aggregation respectively. Harnessing the experience and resources of these successful groups will allow you to develop an extensive state-of-the-art skill-set supported by highly successful and encouraging laboratory groups to tackle a problem of major scientific importance that offers outstanding future career opportunities.
The John Walton Muscular Dystrophy Research Centre is located within the Institute of Translational and Clinical Research, which is part of the International Centre for Life, adjacent to Newcastle Central Station. The Institute of Translational and Clinical Research translates the knowledge gained in the laboratory into new diagnostic tests and treatments which are trialed in clinical studies in patients.
