Muscle: Form and Function

The Muscle: Form and Function group is made up of biomedical scientists and physiologists whose research programmes range from cell and molecular biology and physiology to whole-body systems and integrative physiology. Focus is on striated (skeletal and cardiac) muscle with exercise, ageing and health as cross-cutting themes.

Research areas include:

Physiological cardiac remodelling to improve repair and regeneration.
The role of ageing in the regenerative capacity of the heart and skeletal muscle.
Congenital myopathies: From mutations to treatment.
Regulation of cardiac and skeletal muscle contractility by the thick filament in health, ageing and disease.
The effects of healthy ageing on muscle structure and function
The effects of critical illness on muscle
The interaction of exercise and nutrition in regulating skeletal muscle protein turnover.

Members

Georgina Ellison-Hughes

Professor of Regenerative Muscle Physiology

Luca Fusi

Sir Henry Dale Fellow

Stephen Harridge

Professor of Human & Applied Physiology

Julien Ochala

Reader in Muscle Physiology

Ross Pollock

Lecturer in Aerospace Physiology

Oliver Witard

Senior Lecturer in Exercise Metabolism & Nutrition

Can senolytics rejuvenate the regenerative capacity of the heart

Senescent cells have emerged as bona fide drivers of ageing and age-related cardiovascular disease, with senescent cells accumulating in the aged heart and following damage/injury. Removal of senescent cells using senolytics can prevent or delay tissue dysfunction, physical dysfunction and extend health- and lifespan. This project investigates the selective effects of cell senescence and senescent cell clearance on cardiomyocytes, endothelial cells and cardiac progenitor cells. The findings of this project may pave the way for the development of senolytics to treat age-related heart disorders and the toxic effects of cancer chemotherapy on the heart. The image to the left shows an increase in the number of proliferating (Ki67-positive) cardiomyocytes following senescent cell clearance by AP or D+Q senolytics in the aged mouse heart. Figure adapted from Lewis-McDougall et al. 2019, Aging Cell.

Understanding the mechanisms underlying myosinopathies

Genetic alterations to the genes that encode part of the myosin molecule mean that a faulty (or mutant) protein is made, and this leads to severe muscle weakness in patients, in a type of disease known as myosinopathies. We do not understand how these faulty (or mutant) myosin proteins cause skeletal muscle weakness. Our research helps to obtain a new understanding of how faulty myosin proteins cause myosinopathies. We specifically test how mutations affect the molecular structure of the myosin, how this affects its ability to form precisely built filaments, and how this then results in changes to muscle structure, leading to muscle weakness. Our approaches range from investigating individual fragments of myosin to investigating the organisation and properties of myosin in intact human patient samples to enable us to obtain a deep understanding. The new knowledge acquired will not only greatly advance our understanding of myosinopathies, but, most importantly, suggest pharmacological targets that may be exploited for effective therapeutic interventions.

Thick filament-based mechanisms for the dynamic regulation of contraction and relaxation in the heart

For the last 40 years the regulation of contraction in skeletal and cardiac muscle was thought to be mediated by structural changes in the actin-containing thin filaments linked to the intracellular calcium transient. However, recently it has become clear that, whilst the canonical calcium/thin filament-based pathway provides a start signal for contraction in skeletal muscle, its strength and speed are largely controlled by structural changes in the myosin-containing thick filaments. In this project we use a fluorescence-based approach to characterise the structural dynamics of thin and thick filaments during activation and relaxation of isolated cardiac trabeculae and cardiac myofibrils. The image to the left shows a cardiomyocyte in a cardiac trabecula from a rat heart. Red, α-actinin in the Z-band of the sarcomere; green, myosin-binding protein C, a fundamental regulatory protein of the thick filament.

Effects of healthy ageing on skeletal muscle

Muscle mass and function decline with age, which when certain threshold are crossed, becomes termed “sarcopenia”. However, in addition to ageing processes, muscle is also affected by usage. With levels of physical activity markedly declining as people get older, it remains unclear the extent to which the decline in muscle form and function is due to inherent ageing effects or to an interaction of ageing and inactivity mediated processes. This project is taking a multi-faceted (stem cell, multi-omics, through to in vivo function) approach and both cross-sectional and longitudinal study designs, investigating young and old exercisers (master cyclists) and sedentary individuals. The aim is to identify which aspects of muscle are affected by age, inactivity (or both) and the extent to which muscle quality and function might be maintained by exercise. The image to the left shows a magnetic resonance image taken through the mid-thigh region of a highly active cyclist aged 83 years. The scan shows no signs of the decline (marked loss of tissue mass, infiltration with fat and connective tissue) typically seen in a sarcopenic muscle.

Effect of 𝛽 −Lactoglobulin supplementation as a preoperative therapy in older people with osteoarthritis undergoing hip replacement surgery

Osteoarthritis is an inflammatory condition that is prevalent in older adults at risk of underlying sarcopenia (low muscle volume and strength). An important clinical implication of hip osteoarthritis is the loss of skeletal muscle mass and strength; an issue exacerbated during hip replacement surgery. To address this clinical problem, the field of perioperative medicine continues to evolve. The aim is to establish best practice therapeutic strategies for patients before, during and after surgery. This inter-disciplinary (clinical nutrition, physiology, biomechanics, perioperative clinical medicine, and public and patient) project will investigate the feasibility of conducting a randomized controlled trial to evaluate the effectiveness of ß-Lactoglobulin supplementation as a novel perioperative strategy to improve musculoskeletal health outcomes following hip replacement surgery in older people with osteoarthritis

Brunello E, Fusi L, Ghisleni A, Park-Holohan S-J, Ovejero JG, Narayanan T and Irving M. Myosin filament-based regulation of the dynamics of contraction in heart muscle. PNAS 117, 8177-8186, doi:10.1073/pnas.1920632117 (2020).

Cottle BJ, Lewis FC, Shone V, Ellison-Hughes GM. (2017) Skeletal muscle-derived interstitial progenitor cells (PICs) display stem cell properties, being clonogenic, self-renewing and multi-potent in vitro and in vivo. Stem Cell Research & Therapy. 8:158. doi: 10.1186/s13287-017-0612-4.

Duggal NA, Pollock RD, Lazarus NR, Harridge SDR, Lord JM (2018) Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging Cell 17(2):e12750. doi: 10.1111/acel.12750.

Ispoglou T, Witard OC, Duckworth LC, Lees MJ. The efficacy of essential amino acid supplementation for augmenting dietary protein intake in older adults: implications for skeletal muscle mass, strength and function. Proc Nutr Soc. 2021 May;80(2):230-242. doi: 10.1017/S0029665120008010. Epub 2020 Dec 14.PMID: 33315000 Review.

Jungbluth H, Treves S, Zorzato F, Sarkozy A, Ochala J, Sewry C, Phadke R, Gautel M, Muntoni F. Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction. Nat Rev Neurol. 2018 Mar;14(3):151-167. doi: 10.1038/nrneurol.2017.191. Epub 2018 Feb 2. PMID: 29391587.

Lewis-McDougall FC, Ruchaya PJ, Domenjo-Vila E, Teoh TS, Prata L, Cottle BJ, Clark JE, Punjabi PP, Awad W, Torella D, Tchkonia T, Kirkland J, Ellison-Hughes GM. (2019) Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 18: e12931.DOI: 10.1111/acel.12931.

Park-Holohan SJ, Brunello E, Kampourakis T, Rees M, Irving M and Fusi L. Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing. PNAS 118, doi:10.1073/pnas.2023706118 (2021).

Pollock RD, O'Brien KA, Daniels LJ, Nielsen KB, Rowlerson A, Duggal NA, Lazarus NR, Lord JM, Philp A, Harridge SDR (2018) Properties of the vastus lateralis muscle in relation to age and physiological function in master cyclists aged 55-79 years. Aging Cell. 17(2):e12735. doi: 10.1111/acel.12735.

Pollock RD, Carter S, Velloso CP, Duggal NA, Lord JM, Lazarus NR, Harridge SDR (2015) An investigation into the relationship between age and physiological function in highly active older adults. J Physiol. 593(3):657-80 . doi: 10.1113/jphysiol.2014.282863.

Ross JA, Levy Y, Ripolone M, Kolb JS, Turmaine M, Holt M, Lindqvist J, Claeys KG, Weis J, Monforte M, Tasca G, Moggio M, Figeac N, Zammit PS, Jungbluth H, Fiorillo C, Vissing J, Witting N, Granzier H, Zanoteli E, Hardeman EC, Wallgren-Pettersson C, Ochala J. Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy. Acta Neuropathol. 2019 Sep;138(3):477-495. doi: 10.1007/s00401-019-02034-8. Epub 2019 Jun 19. PMID: 31218456; PMCID: PMC6689292.

Scalise M, Torella M, Marino F, Ravo M, Giurato G, Vicinanza C, Cianflone E, Mancuso T, Aquila I, Salerno L, Nassa G, Agosti V, De Angelis A, Urbanek K, Veltri P, Paolino D, Mastroroberto P, De Feo M, Viglietto G, Weisz A, Nadal-Ginard B, Ellison-Hughes GM, Torella D. (2020) Atrial Myxomas Arise From Multipotent Cardiac Stem Cells. European Heart Journal. 41:4332-4345.

Witard OC, McGlory C, Hamilton DL, Phillips SM. Growing older with health and vitality: a nexus of physical activity, exercise and nutrition. Biogerontology. 2016 Jun;17(3):529-46. doi: 10.1007/s10522-016-9637-9. Epub 2016 Feb 15.PMID: 26878863 Free PMC article. Review.

Zaromskyte G, Prokopidis K, Ioannidis T, Tipton KD, Witard OC. Evaluating the Leucine Trigger Hypothesis to Explain the Post-prandial Regulation of Muscle Protein Synthesis in Young and Older Adults: A Systematic Review. Front Nutr. 2021 Jul 8;8:685165. doi: 10.3389/fnut.2021.685165. eCollection 2021.PMID: 34307436 Free PMC article.

Academic staff:

Norman Lazarus (Emeritus)

Post-doctoral researchers

Tom Francis

Piotr Sunderland

Hannah Dugdale

Abeer Shaalan

Research assistants:

Leah Siegel

Eloise Milbourn

PhD students:

Yu Han