Dr Paul Gregorevic
Head, Muscle Research and Therapeutics Laboratory
NHMRC RD Wright Biomedical Career Development Fellow
Phone: +61 3 8532 1224
Using gene transfer technology to study muscle diseases
Skeletal muscle accounts for almost half a person's body mass, yet we easily take for granted its role in our health and lifestyle. The reality is that physical frailty caused by a loss of strength is the primary cause of death among a significant proportion of the elderly population, and patients with a host of medical conditions. Even a moderate decline in muscle strength caused by advancing age, bed rest or inactive lifestyle can dramatically increase the incidence and severity of many serious medical conditions.
The goal of the Laboratory for Muscle Research and Therapeutics is to understand the cellular mechanisms that regulate muscle growth, wasting and metabolism, so that we can develop new methods of preventing or treating the symptoms of muscle-related diseases. Our studies also consider these mechanisms in the context of cardiac muscle adaptation, and heart disease.
The research places a particular emphasis on employing recombinant viral vectors designed and manufactured in-house as a means to selectively alter gene expression in mouse models, and analyses using a host of established and cutting-edge techniques spanning the disciplines of biological/biomedical science. Employing the advantages of gene delivery technologies this way enables us to interrogate the cellular mechanisms controlling muscle adaptation in vivo with a combination of speed, precision, and efficacy not attained using other approaches.
The transforming growth factor-β (TGFβ) signaling network is one of the most important regulators of muscle development and post-natal adaptation. We have shown that individual TGFβ superfamily ligands influence intramuscular signalling differently to promote wasting and growth. Our research is dissecting the specific elements of the system that contribute to growth vs. wasting, and investigating how we can manipulate TGFβ signalling from within to counter muscle wasting.
Stimulation of the β-adrenergic signalling pathway promotes protein synthesis and inhibits protein degradation in muscle, but administering drugs to activate this pathway may prove challenging in the clinic because of the risks of adverse effects in other tissues. We have found that we can use gene therapy tools to activate this pathway and promote muscle growth in the absence of administering drugs. We are testing strategies that manipulate this pathway as prospective muscle therapeutics.
Different modes of skeletal muscle growth and wasting uniquely alter gene expression. We are seeking to define distinct and common programs of gene expression associated with muscle growth and wasting states, to identify key mechanisms that govern muscle mass, functional capacity and metabolism. We are using viral vectors to manipulate the expression of specific genes, and dissect the key processes that control muscle adaption.
The discovery of non-coding RNAs has revised our understanding of cell biology. Families of non-coding RNAs are differentially expressed in skeletal muscle during development, adaptation and muscle disease, but their biological functions are poorly understood. We are investigating the expression and roles of non-coding RNAs in skeletal muscle, and evaluating the therapeutic potential of manipulating non-coding RNA activity in skeletal muscle.
Interventions for muscle-related diseases can correct the primary defect, or counter the development of pathology via other mechanisms. We have used viral-vector interventions to increase muscle mass and function in mice modelling a variety of muscle diseases. We are now exploring how to enhance the therapeutic potential of our most promising interventions.
Type 2 diabetes is one of the world's fastest growing health problems. Using a gene therapy-based strategy to express specific proteins from skeletal muscles, we have found we can improve many of the most important features of diabetic pathology in mice. We are now investigating how to enhance and develop the therapeutic potential of this approach.
Dr Gregorevic gained his PhD from the University of Melbourne Department of Physiology in 2001. He subsequently trained as a postdoctoral research fellow within the University of Washington Department of Neurology, Seattle USA, where he acquired expertise in molecular biology and the design of recombinant viral vectors as gene delivery technologies for studying and treating muscle diseases. In 2008, Dr Gregorevic relocated his research program to Baker IDI Heart and Diabetes Institute, Melbourne, where he is Head of the Laboratory for Muscle Biology and Therapeutics Development, and Director of the Recombinant Viral Vector Core. His research interests focus on elucidating the mechanisms underlying the development and regulation of the skeletal muscle phenotype, and the development of novel therapeutic interventions to combat loss of muscle function associated with heritable and acquired diseases and the aging process. Dr Gregorevic has authored numerous papers, reviews and book chapters concerning the mechanisms of skeletal muscle function and adaptation, neuromuscular disorders, and intervention strategies for their treatment. He has served as an elected member of the Executive Committee of the Australian Gene Therapy Society since 2009.
Chen JL, Walton KL, Al-Musawi SL, Kelly EK, Qian, H, La M, Lu L, Lovrecz G, Ziemann M, Lazarus, R, El-Osta A, Gregorevic P*, Harrison, C*. Development of novel activin-targeted therapeutics. Mol Ther 2014; in press. *contributed equally to the work.
Chen JL, Walton KL, Winbanks CE, Murphy KT, Thomson RE, Makanji Y, Qian H, Lynch GS, Harrison CA, Gregorevic P. Elevated expression of activins promotes muscle wasting and cachexia. FASEB J 2014;28(4):1711-23.
Winbanks CE, Chen JL, Qian H, Liu Y, Bernardo BC, Beyer C, Watt KI, Thomson RE, Connor T, Turner BJ, McMullen JR, Larsson L, McGee SL, Harrison CA, Gregorevic P. The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell Biol 2013;203(2):345-57.
Seto JT, Quinlan KG, Lek M, Zheng XF, Garton F, MacArthur DG, Hogarth MW, Houweling PJ, Gregorevic P, Turner N, Cooney GJ, Yang N, North KN. ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling. J Clin Invest 2013;123(10):4255-63.
Winbanks CE, Beyer C, Hagg A, Qian H, Sepulveda PV, Gregorevic P. miR-206 represses hypertrophy of myogenic cells but not muscle fibers via inhibition of HDAC4. PLoS One 2013;8(9):e73589.
Winbanks CE, Weeks KL, Thomson RE, Sepulveda PV, Beyer C, Qian H, Chen JL, Allen JM, Lancaster GI, Febbraio MA, Harrison CA, McMullen JR, Chamberlain JS, Gregorevic P. Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. J Cell Biol 2012;197:997-1008.
Winbanks CE, Beyer C, Qian H, Gregorevic P. Transduction of skeletal muscles with common reporter genes can promote muscle fiber degeneration and inflammation. PLoS One 2012;7:e51627.
Bernardo BC, Gao XM, Winbanks CE, Boey EJ, Tham YK, Kiriazis H, Gregorevic P, Obad S, Kauppinen S, Du XJ, Lin RC, McMullen JR. Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci USA 2012;109:17615-20.
Weeks KL, Gao X, Du XJ, Boey EJ, Matsumoto A, Bernardo BC, Kiriazis H, Cemerlang N, Tan JW, Tham YK, Franke TF, Qian H, Bogoyevitch MA, Woodcock EA, Febbraio MA, Gregorevic P, McMullen JR. Phosphoinositide 3-kinase p110α is a master regulator of exercise-induced cardioprotection and PI3K gene therapy rescues cardiac dysfunction. Circ Heart Fail 2012;5:523-34.
Winbanks CE, Wang B, Beyer C, Koh P, White L, Kantharidis P, Gregorevic P. TGF-beta regulates miR-206 and miR-29 to control myogenic differentiation through regulation of HDAC4. J Biol Chem 2011;286:13805-14
Odom GL, Gregorevic P, Allen JM, Chamberlain JS. Gene therapy of mdx mice with large truncated dystrophins generated by recombination using rAAV6. Mol Ther 2011;19:36-45.
Gregorevic P, Schultz BR, Allen JM, Halldorson JB, Blankinship MJ, Meznarich NA, Kuhr CS, Doremus C, Finn E, Liggitt D, Chamberlain JS. Evaluation of vascular delivery methodologies to enhance rAAV6-mediated gene transfer to canine striated musculature. Mol Ther 2009;17:1427-33.
Gregorevic P, Allen JM, Minami E, Blankinship MJ, Haraguchi M, Meuse L, Finn E, Adams ME, Froehner SC, Murry CE, Chamberlain JS. rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat Med 2006;12:787-9.
Gregorevic P, Blankinship MJ, Allen JM, Crawford RW, Meuse L, Miller DG, Russell DW, Chamberlain JS. Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med 2004;10:828-34.
Blankinship MJ, Gregorevic P, Allen JM, Harper SQ, Harper H, Halbert CL, Miller AD, Chamberlain JS. Efficient transduction of skeletal muscle using vectors based on adeno-associated virus serotype 6. Mol Ther 2004;10:671-8.
Justin Chen, PhD (postdoctoral research fellow)
Jonathan Davey, PhD (postdoctoral research fellow)
Kevin Watt, PhD (postdoctoral research fellow)
Hongwei Qian, PhD (research scientist)
Adam Hagg, MSc (research assistant)
Rachel Thomson, PhD (research assistant)
Timothy Colgan (PhD student)
Queenie Lee (BSc Hons student)