Research Vision

Our laboratory investigates the mechanisms underlying skeletal muscle wasting and weakness and develops and tests therapies to counteract muscle wasting disorders.

The laboratory’s research is focused on ageing (sarcopenia), muscle diseases (such as the muscular dystrophies), and cancer cachexia.  We also investigate novel approaches for improving muscle repair after injury. We also investigate novel approaches for improving muscle repair after injury.

Our work has application for many other muscle wasting conditions including: sepsis and other forms of metabolic stress; denervation, disuse, inactivity, unloading or microgravity; burns, human immunodeficiency virus (HIV)-acquired immunodeficiency syndrome; chronic kidney or heart failure; and chronic obstructive pulmonary disease.

Our studies involve investigation of molecular pathways regulating muscle size and function with a translational approach of cell culture experiments complemented by studies utilizing different animal models for these muscle wasting conditions.

Our ultimate goal is to apply this information to human patients in collaborative studies with orthodontists and maxillofacial surgeons, anaesthetists, critical care physicians, and plastic and reconstructive surgeons.

2009 B&CM Laboratory Research Profiles

Basic and Clinical Myology Laboratory (2009) - [Back row, from left] Mr. Tim Naim (research assistant), Mr. Nic Tirtaatmadja (PhD student), Dr. Chris van der Poel (Research Officer), Dr. René Koopman (Research Fellow), Mr. Tim Sayer (Honours student), Mr. Ben Gleeson (research assistant); [Middle row, from left] Ms. Jennifer Trieu (research assistant), Ms Annabel Chee (Honours student), Prof. Gordon Lynch (laboratory head), Ms. Fiona Colarossi (laboratory manager), Mr. Marc Nicolas (PhD student), Dr. Kate Murphy (Research Fellow); [Front row, from left] Dr. Jarrod Church (Senior Research Officer), Mr. Daniel Ham (PhD student), Dr. Brendan Adams (Research Officer), Mr. Stefan Gehrig (PhD student), Dr. Bertrand Leger (Honorary Research Fellow). Absent - Miss. Sarah Turpin (PhD student).

Latest News

• August 2009
• Congratulations to Prof. Gordon Lynch for his Citation from the Australian Learning and Teaching Council for Outstanding Contributions to Student Learning. This award recognises his over 15 years of sustained excellence in supervision, support and mentoring of undergraduate and postgraduate scholars on their research journeys in the biomedical sciences. (www.altc.edu.au).
• July 2009
• Congratulations to Dr. Jonathan Schertzer who was awarded a Canadian Institutes of Health Research Fellowship and the Banting and Best Research Fellowship from the Banting and Best Diabetes Centre in Canada. On top of his recent De Groote Fellowship for a tenure-track appointment at McMaster University (Canada), that makes three from three! A really great effort and most thoroughly deserved. Warm congratulations to you Jon from all of us in the lab.
• May 2009
• Dr. Jonathan Schertzer has been awarded The DeGroote Academic Fellowship designed to stream into a tenure-track Assistant Professor position in the Faculty of Medicine at McMaster University, Canada. Congratulations Jon on your success – which is most thoroughly deserved!
• Congratulations to Radhika Sheorey for being awarded the Deans Honours List Award for her Honours mark last year. A terrific and very well-deserved achievement! Congratulations also to her supervisors Jarrod, Gordon and James for their contributions.
• December 2008
• Congratulations to Dr. Robert Mayne for successful completion of his Doctor of Clinical Dentistry.
• Dr. Jonathan Schertzer was awarded the Chancellor’s Prize (Medicine) from the University – based on the quality of the research published from his Ph.D. thesis.
• Dr. Jonathan Schertzer was awarded the Dean’s Award for Excellence in a Ph.D. thesis.
• Dr. Jonathan Schertzer was awarded the 2008 Postdoctoral Publication Award from the Australian Physiological Society.
• Dr. James Ryall was awarded the 2008 A.K. McIntyre Medal from the Australian Physiological Society for outstanding contributions to Australian physiology by a young investigator over their predoctoral and early postdoctoral years.
• Stefan Gehrig was awarded the best Student Speaker Award at the Australian Physiological Society annual meeting in Melbourne, December 2008
• Stefan Gehrig was awarded a National Heart Foundation Postgraduate Scholarship
• Dr. René Koopman was successful in being awarded an Ajinomoto Amino Acid Research Program (3ARP), Ajinomoto, Japan. Project title: Citrulline as a pharmaco-nutrient to attenuate muscle wasting.
• Dr. Jarrod Church and Prof. Gordon Lynch have been awarded a Rebecca L. Cooper Medical Research Foundation award. Project title: Investigating the potential for erectile dysfunction drugs to enhance the repair of injured skeletal muscles in the elderly.
• Dr. Kate Murphy was awarded an Australian Association of Gerontology Inc. R.M. Gibson Scientific Research Fund award. Project title: Smad7 over-expression: a novel therapy for attenuating ageing-related muscle weakness.
• Stefan Gehrig awarded second prize in the Under the Coverslip ~ Imaging and Microscopy Competition for "Where's Wally"

2009 Student Research Projects

Mr. Stefan Gehrig (PhD project) - The role of IGF binding proteins in IGF-I mediated signalling in the mdx dystrophic mouse.

Mr. Nicolin Tirtaatmadja (PhD project) -Biomolecule Delivery Systems for Tissue Engineering and Skeletal Muscle Regeneration.

Mr. Daniel Ham (PhD project) - Skeletal muscle modifications with exercise and ergogenic supplements.

Mr. Marc Nicolas (PhD project) - Role of beta-adrenergic signalling in skeletal muscle regeneration.

Mr. Tim Sayer (Honours project) - Effect of Hsp70 overexpression on EC coupling of dystrophic mice.

Ms Annabel Chee (Honours project) - Effect of myostatin inhibition on attenuating cancer cachexia.

A single muscle fibre expressing green fluorescent protein. Nuclei have been labelled with ethidium bromide and appear yellow.

Collaborators

• Prof. Christopher Christophi (Department of Surgery, Austin Hospital, The University of Melbourne). Understanding the mechanisms underlying cancer cachexia and evaluating novel treatments for cachexia.
• Dr. Matt Perugini (Bio21 Institute, Department of Biochemistry and Molecular Biology, The University of Melbourne). Using structural biochemistry to characterise protein biomarkers in skeletal muscle biology.
• Dr. Paul Gregorevic (Baker IDI Heart and Diabetes Institute). Gene therapy and skeletal muscle.
• Dr. Craig Harrison (Prince Henry’s Institute of Medical Research, Victoria, Australia). TGF-beta signalling in muscular dystrophy.
• Dr. Aaron Russell (School of Exercise and Nutrition Sciences, Deakin University, Victoria, Australia). Role of Notch signalling in muscle health and disease.
• Dr. Stéphane Walrand & Prof. Yves Boirie (Human Nutrition, Unit, INRA Clermont-Ferrand, France). Citrulline as a pharmaco-nutrient to attenuate muscle wasting.
• Prof. Luc Cynober (Nutrition Laboratory, Pharmacy Faculty, University of Paris). Citrulline as a pharmaco-nutrient to attenuate muscle wasting.
• Prof. João Bizario (Associação de Amigos dos Portadores de Distrofia Muscular, São Paulo, Brazil). Characterisation of the Golden Retriver model of muscular dystrophy.
• Prof. Miranda Grounds (University of Western Australia). Functional regeneration in skeletal muscles during ageing and in muscular dystrophy.
• Prof. Mark Hargreaves (Department of Physiology, The University of Melbourne). Functional and metabolic characteristics of artificial skeletal muscles.
• Dr. Glenn McConnell (Department of Physiology, The University of Melbourne). nNOS signalling in skeletal muscle regeneration.
• Prof. Edna Hardeman & Dr. Anthony Kee (Department of Anatomy, School of Medical Sciences, University of New South Wales, Sydney). Role of cytoskeletal proteins in skeletal muscle contraction.
• Prof. David A. Williams (Department of Physiology, The University of Melbourne). In situ and in vitro skeletal muscle calcium imaging.
• Prof. Bruce E. Kemp, Dr. Belinda Michell & Dr. Greg Steinberg (St. Vincent’s Hospital Research Institute, The University of Melbourne). AMP-kinase during intense muscle activity; calcineurin activity in skeletal muscle; aging and skeletal muscle metabolism.
• Prof. Wayne A. Morrison (Bernard O’Brien Institute for Microsurgery, The University of Melbourne). Improving skeletal muscle repair after ischaemia-reperfusion injury.
• Prof. George E. Muscat (Institute for Molecular Bioscience, The University of Queensland). Nuclear hormone receptors and skeletal muscle.
• Prof. Eric Olson & Assoc. Prof. Rhonda Bassel-Duby (University of Texas-Southwestern, U.S.A.). Role of the calcineurin signal transduction pathway in muscle regeneration and muscular dystrophy.
• Prof. Martin N. Sillence (Queensland University of Technology, Qld.). b₂-adrenoceptors, b₂-agonists and skeletal muscle function.
• Prof. Geoff W. Stevens & Dr. Andrea O'Connor (Department of Chemical & Biomolecular Engineering, The University of Melbourne). Interactions between the interfaces of solid-liquid and liquid-liquid systems for the dispersion of novel growth factors.
• Assoc. Prof. Matthew J. Watt (Department of Physiology, Monash University). Molecular and cell biology of lipid metabolism.
• Prof. Michael G. Woods (School of Dentistry, The University of Melbourne). Functional properties of human facial muscles and their relation to clinical dentistry.
• Prof. Jeffrey Zajac & Dr. Helen Maclean (Department of Medicine Austin and Repatriation Hospital). Androgens and skeletal muscle function.
• Assoc. Prof. Luc Gosselin (Exercise and Nutrition Sciences, University at Buffalo, The State University of New York). Ageing, inflammation and muscle repair.
• Prof. Mark Febbraio (Baker IDI Heart and Diabetes Institute). Role of heat shock proteins in muscle damage and repair in muscular dystrophy.

Current Funding

2008-10

NHMRC

G.S. Lynch, P. Gregorevic

2007-09

ARC

G.S. Lynch, D.A. Williams

2007-09

NHMRC

G.S. Lynch, W.A. Morrison, G.W. Stevens

Recent B&CM Laboratory Publications

2009

Ryall JG, Church JE, Lynch GS. (2009). A novel role for beta-adrenceptor signalling in skeeltal muscle growth, development and regeneration. Clin Exp Pharmacol Physiol. (in press).

Koopman R, Ryall JG, Church JE, Lynch GS. (2009). The role of beta-adrenoceptor signaling in skeletal muscle: therapeutic implications for muscle wasting disorders. Curr Opin Clin Nutr Metab Care. (in press).

Huijsman E, van de Par C, Economou C, van der Poel C, Lynch GS, Schoiswohl G, Haemmerle G, Zechner R, Watt MJ. (2009). Adipose triacylglycerol lipase deletion alters whole body energy metabolism and impairs exercise performance in mice. Am J Physiol Endocrinol Metab.297(2):E505-13.

Turpin SM, Ryall JG, Southgate R, Darby I, Hevener AL, Febbraio MA, Kemp BE, Lynch GS, Watt MJ. (2009). Examination of 'lipotoxicity' in skeletal muscle of high-fat fed and ob/ob mice. J Physiol. 1;587(Pt 7):1593-605.

Porrello ER, Bell JR, Schertzer JD, Curl CL, McMullen JR, Mellor KM, Ritchie RH, Lynch GS, Harrap SB, Thomas WG, Delbridge LM. (2009). Heritable pathologic cardiac hypertrophy in adulthood is preceded by neonatal cardiac growth restriction. Am J Physiol Regul Integr Comp Physiol. 296(3):R672-80.

Vlahovich N, Kee AJ, Van der Poel C, Kettle E, Hernandez-Deviez D, Lucas C, Lynch GS, Parton RG, Gunning PW, Hardeman EC. (2008). Cytoskeletal Tropomyosin Tm5NM1 Is Required for Normal Excitation-contraction Coupling in Skeletal Muscle. Mol Biol Cell. 20(1):400-9.

2008

Lynch GS. (2008). Update on emerging drugs for sarcopenia - age-related muscle wasting. Expert Opin Emerg Drugs.13(4): 655-73.

MacLean, H.E., Chiu, M.W.S., Notini, A.J., Axell, A-M, Davey, R.A., McManus, J.F., Ma, C., Plant, D.R., Lynch, G.S. & Zajac, J.D. (2008). Impaired skeletal muscle mass and function in male but not female androgen receptor knockout mice. FASEB J. 22: 2676-2689

Dzamko N, Schertzer JD, Ryall JG, Steel R, Macaulay SL, Wee S, Chen ZP, Michell BJ, Oakhill JS, Watt MJ, Jørgensen SB, Lynch GS, Kemp BE, Steinberg GR. (2008). AMPK-independent pathways regulate skeletal muscle fatty acid oxidation. J Physiol. 586(Pt 23): 5819-31.

Pearen, M.A., Myers, S., Ryall, J.G., Lynch, G.S. & Muscat, G.E.O. (2008). The orphan nuclear receptor, NOR-1, regulates gene expression that controls oxidative metabolism in skeletal muscle. Endocrinology. 149: 2853-2865

Ryall JG, Lynch GS. (2008). The potential and the pitfalls of beta-adrenoceptor agonists for the management of skeletal muscle wasting. Pharmacol Ther. 120(3) :219-32.

Schertzer JD. & Lynch GS. (2008). Plasmid-based gene transfer in mouse skeletal muscle by electroporation. Methods Mol Biol. 433: 115-25.

Gehrig SM, Ryall JG, Schertzer JD, Lynch GS. (2008). IGF-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage. Exp. Physiol. 93(11):1190-8.

Lynch GS, Faulkner JA, Brooks SV. (2008). Force deficits and breakage rates after single lengthening contractions of single fast fibers from unconditioned and conditioned muscles of young and old rats. Am. J. Physiol. Cell Physiol. 295: C249-C256.

Grounds MD, Radley HG, Lynch GS, Nagaraju K, De Luca A. (2008). Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol Dis. 31: 1-19.

Lynch GS, Schertzer JD, Ryall JG. (2008). Anabolic agents for improving muscle regeneration and function after injury. Clin. Exper. Pharmacol. Physiol. 35: 852-858.

Ryall JG, Schertzer JD, Murphy KT, Allen AM & Lynch GS (2008). Chronic b₂-adrenoceptor stimulation impairs cardiac relaxation via reduced SR Ca²⁺-ATPase activity. Am. J. Physiol. Heart Circ. Physiol.294: H2587-H2595.

Ryall JG, Schertzer JD, Alabakis TM, Gehrig SM, Plant DR & Lynch GS (2008). Intramuscular b₂-agonist administration enhances regeneration and functional repair after myotoxic injury in rat skeletal muscle. J. Appl. Physiol.105: 165-172.

**Ryall JG, Schertzer JD & Lynch GS (2008). Cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness. Biogerontol.9: 213-228.

Stupka N, Schertzer JD, Bassel-Duby R, Olson EN & Lynch GS (2008). Stimulation of calcineurin-Aa activity attenuates muscle pathophysiology in mdx dystrophic mice. Am. J. Physiol. Reg. Int. Comp. Physiol. 294: R983-R992.

Schertzer JD*, van der Poel C*, Shavlakadze T, Grounds MD & Lynch GS (2008). Muscle specific overexpression of IGF-I improves E-C coupling in skeletal muscle fibers from dystrophic mdx mice. Am. J. Physiol. Cell. Physiol. 294:C161-168. [*- these authors contributed equally to this manuscript]

**Lynch GS & Ryall JG (2008). Role of b-adrenoceptor signaling in skeletal muscle: Implications for muscle wasting and disease. Physiol. Rev. 88:729-767.

Book Chapters

Schertzer JD, & Lynch GS (2008). Methods for optimising non-viral ectopic gene expression in normal and regenerating muscle. In (ed) Le Doux JM Gene Therapy Protocols Humana Press, 115-125.

Experimental Techniques

Muscle functional testing

Intact skeletal muscles – We examine the contractile properties of different muscles of rats or mice using in situ (with an intact nerve and blood supply) or in vitro methods. The muscles most commonly assessed are the extensor digitorum longus (EDL) representative of a fast-twitch muscle and the soleus muscle which is representative of a slow-twitch muscle. We typically assess the tibialis anterior muscle using an in situ approach and study the contractile properties of isolated diaphragm muscle strips in vitro.

Single muscle fibres (cells) – Segments of single muscle cells (i.e. muscle fibres) can be carefully dissected from intact muscles (of rats and mice) or from open- or needle-biopsies from animals or humans. We attach these isolated muscle fibre segments to sensitive force transducers and servomotors to assess the contractile properties of skeletal muscle at the cellular level.

Cell lines - (C2C12 & L6) and primary myoblasts

Immunohistochemistry - intracellular localization of proteins

Immunocytochemistry - intracellular localization of proteins

Myoblasts differentiating into myotubes in culture. To form new muscle, myoblasts (muscle precursor cells) proliferate and then fuse together to form multinucleated muscle fibres. We can examine the ability of various therapeutic compounds to enhance either myoblast proliferation or myoblast fusion.

Current Animal Models

The laboratory utilises a number of animal models to study muscular dystrophy and ageing, including;

• mdx - the mdx mouse arose from a spontaneous mutation in the gene encoding the dystrophin gene (located on the X chromosome) in the C57Bl10 mouse. The mdx mouse is the most commonly studied model of Duchene muscular dystrophy (DMD).
• Adrb null - mice that are gentically null for the β₁-adrenoceptor (Adrb1-/-), the β₂-adrenoceptor (Adrb2-/-), or both (Adrb1/2-/-)
• dko - the utrophin null dystrophic mdx mouse (mdx/utrn^-/-) known as the double knock out (dko) mouse. dko mice lack both dystrophin and utrophin (structural/signalling proteins linked to the muscle membrane) which causes muscular dystrophy similar to humans suffering DMD.
• F344 - the Fischer 344 (F344) rat is traditionally used in studies investigating the effect of ageing on skeletal muscle. The F344 rat is generally considered ‘old’ after the age of 24 months, and shows severe age related muscle wasting and weakness (termed ‘sarcopenia’) after the age of 28 months.

Alumni

Postdoctoral Researchers:

• Dr. Paul Gregorevic (Pfizer Australia Senior Research Fellow, Laboratory for Muscle Research and Therapeutics Development, The Baker Heart Research Institute, Melbourne, VIC, Australia)
• Dr. David R. Plant (Senior Regulatory Affairs Associate, CSL Limited, Melbourne, VIC, Australia)
• Dr. Jonathan D. Schertzer (NSERC Research Fellow, The Hospital for Sick Children, Ontario, Canada)
• Dr. James G. Ryall (CJ Martin Fellow, The Laboratory of Muscle Stem Cells and Gene Regulation, NIH, MD, USA)
• Dr. Brendan Adams (Lecturer, Charles Sturt University, Wagga Wagga, NSW, Australia)

Ph.D. students:

• Dr. Noel D. Duncan (Executive Director, Health1st Pty. Ltd. T/A Fitness2live, London, UK)
• Dr. Siun P. O'Sullivan (Lecturer, Biomedical Sciences, Victoria University of Technology, Melbourne, VIC, Australia)
• Dr. Paul Gregorevic (Pfizer Australia Senior Research Fellow, Laboratory for Muscle Research and Therapeutics Development, The Baker Heart Research Institute, Melbourne, VIC, Australia)
• Dr. David R. Plant (Senior Regulatory Affairs Associate, CSL Limited, Melbourne, VIC, Australia)
• Dr. James G. Ryall (CJ Martin Fellow, The Laboratory of Muscle Stem Cells and Gene Regulation, NIH, MD, USA)
• Dr. Nicole Stupka (Peter Doherty Fellow, Deakin University, Melbourne, VIC, Australia)
• Dr. Jonathan D. Schertzer (Postdoctoral Researcher, The Hospital for Sick Children, Ontario, Canada)
• Dr. Felice Beitzel (training for the Winter Olympics in Bend, Oregon)

Miss. Sarah Snell (2008)

Visitors/Sabbaticals

November-April 2000: Prof. Bartley R. Frueh, Kellogg Eye Center, Department of Ophthalmology, The University of Michigan.

November-April 2006: A/Prof. Luc Gosselin, Department of Exercise and Nutrition Sciences, University at Buffalo The State University of New York.

Links

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