firstname.lastname@example.orgGrowth, Development and Metabolism Programme
Skeletal muscle is a metabolically active tissue that imparts strength. Although muscle development takes place during embryonic/fetal growth, postnatally skeletal muscle has the ability to repair itself after injury due to the presence of muscle stem cells termed Satellite cells (see Figure 1). Any perturbations in muscle regeneration, leads to muscle wasting conditions that include Atrophy, Cachexia (Muscle wasting due to chronic illness, such as Cancer) and Sarcopenia (Ageing-related muscle wasting). Furthermore, skeletal muscle is a metabolically active tissue and various nutritional stress conditions such as diabetes, reprograms muscle metabolism. Our laboratory has been actively involved in skeletal muscle research for the past 15 years and focus on understanding the role of growth factors not only in regulating postnatal skeletal muscle growth in health and disease but also in muscle metabolism during metabolic syndrome.
We have discovered that, in addition to the positive regulators of myogenesis, there are also several negative regulators of skeletal muscle growth. In 1997, we discovered that a gene mutation in the TGF-b super-family member myostatin, caused a dramatic increase in the growth of prenatal and post natal skeletal muscle (see Figure 2). We have established the function of Myostatin in three independent models namely chicken, mice and cattle and more recently we have also demonstrated the ability of Myostatin to regulate muscle growth using human myoblast cell lines. Thus Myostatin is considered to be a well-conserved potent negative regulator of skeletal muscle myogenesis. Recent research from our lab indicates that Myostatin is expressed in Satellite cells, and regulates Satellite cell biology, including Satellite cell activation and self-renewal as well as specification of the Satellite cell lineage. In addition to regulating muscle growth, we also find that Myostatin significantly regulates lean muscle mass and insulin sensitivity.Currently we are focusing on two main themes in my laboratory. Firstly we focus on understanding the reasons for muscle stem cell ageing and how this in turn initiates skeletal muscle ageing (Sarcopenia) in experimental animals, and in the Singaporean population. Secondly we focus on translational research pertaining to type II diabetes. Moving forward, in collaborations with clinician scientists, we are trying to define the genetic and epigenetic basis for insulin resistance in humans using well characterized human primary myoblast cells established from insulin resistant and insulin sensitive Indian, Malay and Chinese cohorts based in Singapore.
- Genetic basis for muscle stem aging during sarcopenia
- Molecular basis for muscular atrophy
- Stem cell based therapies for skeletal muscle regeneration
- Defining Genetic and epigenetic basis for the development of insulin resistance using well-characterized human myoblasts.
Sudarsanareddy Lokireddy, Ge XiaoJia, Vincent Mouly, Gillian Butler-Browne, Peter D. Gluckman, Mridula Sharma, Ravi Kambadur and Craig McFarlane. (2011). Myostatin promotes the wasting of human myoblast cultures through targeting and degrading sarcomeric proteins. Am J Physiol Cell Physiol. (Communicated) (IF 4.1).
McFarlane, Craig., Gu Zi Hui, Wong Zhi Wei Amanda, Hiu Yeung Lau, Sudarsanareddy Lokireddy, Ge XiaoJia, Vincent Mouly, Gillian Butler-Browne, Peter D. Gluckman, Mridula Sharma and Ravi Kambadur. (2011). Human myostatin negatively regulates human myoblast growth and differentiation. Am J Physiol Cell Physiol. (Accepted) (IF 4.1).
Chen Zhang, Chek Kun Tan, Craig McFarlane, Mridula Sharma, Nguan Soon Tan, Ravi Kambadur. (2011). Myostatin-null mice exhibit delayed skin wound healing through the blockage of transforming growth factor-β signaling by decorin. PloS ONE. (Communicated) (IF 4.4).
Xiaojia Ge, Craig McFarlane, Anuradha Vajjala, Sudarsanareddy Lokireddy, Zhi Hui Ng, Chek Kun TAN, Nguan Soon TAN, Walter Wahli, Mridula Sharma and Ravi Kambadur (2011). Smad3 signaling is required for satellite cell function and myogenic differentiation of Myoblasts. Cell Research (Accepted, In Press) (IF 8.1).
Sudarsanareddy Lokireddy, Craig McFarlane, Xiaojia Ge, Huoming Zhang, Siu Kwan Sze, Mridula Sharma and Ravi Kambadur (2011). Myostatin induces degradation of sarcomeric proteins via a Smad3 signaling mechanism during cachexia. Molecular & Cellular Proteomics. (Communicated) (IF 8.8)
C. Zhang, C. McFarlane, S. Lokireddy, S. Bonala, X. Ge2 S. Masuda, PD. Gluckman1, M. Sharma3 and R. Kambadur (2011). Myostatin deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein Kinase signaling pathway. Diabetologia. (Accepted, available online). (IF 6.5).
Craig McFarlane Mridula Sharma and Ravi Kambadur. Role of myostatin and TGF-beta signaling in skeletal muscle growth and development: implications for sarcopenia. In: Sarcopenia – Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments, edited by Lynch GS, Springer, 2011, p. 419-447.
McFarlane, C., Sharma, M., and Kambadur, R. (2008). Myostatin is a procachectic growth factor during postnatal myogenesis. Curr Opin Clin Nutr Metab Care. 11(4): 422-7 Review.
McFarlane, C., Hennebry, A., Thomas, M., Plummer, E., Ling, N, L., Sharma, M., Kambadur, R. (2008). Myostatin signals through Pax7 to regulate satellite cell self-renewal. Exp. Cell Res. 314(2): 317-29 (IF 3.6).
McFarlane, C., Plummer, E., Thomas, M., Hennebry, A., Ashby, M., Ling, N, L., Smith, H., Sharma, M., Kambadur, R. (2006). Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism. J of Cell Physiol 209:501-514 (IF 4.6).
McFarlane, C., Langley, B., Thomas, M., Hennebry, A., Plummer, E., Nicholas, G., McMahon, C., Sharma, M., Kambadur, R. (2005). Proteolytic processing of myostatin is auto-regulated during myogenesis. Dev Biol 283(1): 58-69. (IF 4.4).
Langley, B., Thomas, M., McFarlane, C., Gilmour, S., Sharma, M., and Kambadur, R. (2004). Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway. Oncogene. 23(2): 524-34 (IF 7.1).
A/Prof. Ravi Kambadur
Senior Principal Investigator