Education

Postdoctoral Fellow
The Salk Institute, 2008
Ph.D.
University of California, Berkeley 2003

Areas of Interests

Research Interests

Harnessing new pathways to improve muscle metabolism and muscle growth

Research Information

Harnessing new pathways to improve muscle metabolism and muscle growth

Our laboratory is dedicated to understanding how cells respond and adapt to stress-induced hormonal changes and how those pathways might become inappropriately activated or inhibited in disease. We focus on hormone-induced changes in gene regulation and the impact of those newly expressed genes on physiology.

How does insulin resistance develop?

Humans require a constant glucose supply to maintain heart and brain function even when food is scarce. On the other hand, excess circulating glucose is detrimental and underlies development of type 2 diabetes. In type 2 diabetes, blood glucose becomes too high in part because liver, muscle and fat tissue become resistant to the hormone insulin. “Insulin resistance” occurs in individuals with clinical pre-diabetes, which affects ~30% of adults in the US, most of whom are undiagnosed. In spite of the prevalence of this disease, few FDA approved drugs attack insulin resistance. Thus, there is an urgent need to identify  “drug-able” proteins to increase the therapeutic options for pre-diabetes.

Our laboratory studies an enzyme (salt inducible kinase 1, or SIK1) that is present throughout the body and participates in fine-tuning hormonal responses. In liver, SIK1 was previously thought to inhibit a key pathway that stimulates new glucose synthesis. Surprisingly, deletion of the SIK1 gene in mice had no affect on liver glucose synthesis. Instead, SIK1-deficient mice were strongly protected from hyperglycemia when fed a high fat diet, even though the mice became just as obese as control animals. We now know that SIK1 is turned up in skeletal muscle of fat mice and that SIK1 inhibits the actions of insulin (Nixon, et al, Mol Met 2016). This makes SIK1 a very promising target for therapeutic development. We are currently investigating why SIK1 abundance is increased in obesity and how this enzyme inhibits insulin action.

How do hormones regulate muscle growth and strength?

One aspect of aging is loss of skeletal muscle mass and strength, which impacts metabolic health as well maintenance of normal daily activities. Our laboratory is undertaking a multi-faceted approach to identify pathways that could be targeted with drugs to help maintain muscle mass through activation of stem cells or promotion of growth, or hypertrophy, of existing muscle. First, we are analyzing the effects of SIK1 on muscle mass because SIK1 responds in different ways to hormones that promote muscle growth and to conditions that promote muscle wasting. We are now testing the impact of genetic SIK1 deletion in mice on muscle mass, muscle strength and exercise ability with aging. Second, we have developed tools to characterize how novel factors released by muscle activate muscle stem cells and study the impact of these pathways on muscle stem cell function and ultimately muscle mass during aging. In addition, we created mice in which we can mimic hormonal pathways that stimulate muscle hypertrophy using an otherwise inert chemical compound. Using these mice and isolated muscle stem cells, we are working to establish a signature of genes and proteins associated with muscle stem cell activity and muscle growth. Finally, we engineered reporter mice that glow in the dark when growth-promoting hormonal pathways are activated. Ultimately we expect to uncover new pathways that could be targeted to promote muscle growth and strength in aging individuals.

Research projects

  • Role of SIK1 in development and severity of type 2 diabetes
  • Regulation of muscle mass and performance by SIK1
  • Chemical-genetic methods to stimulate muscle stem cell proliferation and muscle regeneration to uncover new pathways that promote muscle regeneration and hypertrophy

Publications

Publication Information

REFERENCES

  • Akhmedov D, Kirkby NS, Mitchell JA, and Berdeaux R. (2019).  Imaging of Tissue-specific and Temporal Activation of GPCR Signaling using DREADD Knock-In Mice. Methods in Molecular Biology; 1947: 361-376.
  • Fekry B, Ribas-Latre A, Baumgartner C, Deans J, Kwok C, Patel P, Fu L, Berdeaux R, Sun K, Kolonin M, Wang S, Yoo S-H, Sladek F, and Eckel-Mahan K. (2018). Incompatibility of the Circadian Protein BMAL1 and HNF4alpha in Hepatocellular Carcinoma. Nat Commun, 9(1): 4349.
  • Akhmedov D, Rajendran K, Medonza-Rodriguez M, and Berdeaux R. (2016). Knock-in luciferase reporter mice for in vivo monitoring of CREB activity. PLoS ONE, 11(6):e0158274.
  • Nixon M, Stewart-Fitzgibbon R, Fu J, Akhmedov D, Rajendran K, Mendoza-Rodriguez MG, Rivera-Molina M, Gibson M, Berglund ED, Justice NJ and Berdeaux R. (2016) Skeletal muscle salt inducible kinase 1 promotes insulin resistance in obesity. Molecular Metabolism, 5(1): 34-46.
  • Wong CO, Palmieri M, Li J, Akhmedov D, Chao Y, Broadhead GT, Zhu MX, Berdeaux R, Collins CA, Sardiello M, and Venkatachalam K. (2015). Diminished MTORC1-Dependent JNK-Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction. Cell Rep., Sep 29;12(12):2009-20. doi: 10.1016/j.celrep.2015.08.047. Epub 2015 Sep 17.
  • Zuo, Y., Berdeaux, R., and Frost, J.A. (2014). The RhoGEF Net1 is required for normal mammary gland development. Mol. Endo., 28: 1948-60.
  • Akhmedov, D., and Berdeaux, R. (2013). The effects of obesity on skeletal muscle regeneration. Front Physiol, 4: 371.
  • Chatterjee S, Nam D, Guo B, Kim JM, Wennier GE, Lee J, Berdeaux R, Yechoor VK and Ma K. (2013). Brain and Muscle Arnt-like 1 is a key regulator of myogenesis.J Cell Sci, 126 (Pt 10): 2213-24.
  • Clark RI, Tan S, Péan CB, Roostalu U, Vivancos V, Bronda K, Pilátová M, Fu J, Walker DW, Berdeaux R, Geissmann F and Dionne MS. (2013). Mef2 is an in vivo immune-metabolic switch.Cell, 155(2): 435-447.
  • Fu J, Akhmedov D, and Berdeaux R. (2013). The short isoform of the ubiquitin ligase NEDD4L is a CREB target gene in hepatocytes. PLoS ONE, 8(10): e78522.
  • Stewart R*, Akhmedov D*, Robb C, Leiter C, and Berdeaux R. (2013). Regulation of SIK1 abundance and stability is critical for myogenesis. PNAS 110(1): 117-22. *, equal contribution.
  • Luo J, Stewart R, Berdeaux R and Hu H. (2012). Tonic inhibition of TRPV3 by Mg2+ in mouse epidermal keratinocytes. J Invest Dermatol 132(9): 2158-65.
  • Berdeaux R and Stewart R. (2012).cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. Am J Physiol Endocrinol Metab,  303(1): E1-E17.
  • Stewart R, Flechner L, Montminy M,  Berdeaux R. (2011).CREB Is Activated by Muscle Injury and Promotes Muscle Regeneration. PLoS ONE 6(9): e24714.
  • Berdeaux R (2011). Metabolic regulation by SIK kinases. Front Biol 6(3): 231-241.
  • Song Y, Altarejos J, Goodarzi MO, Inoue H, Guo X, Berdeaux R, Kim JH, Goode J, Igata M, Paz J, Hogan MF, Singh P, Goebel N, Miller N, Cui J, Jones MR, Taylor KD, Hsueh WA, Rotter JI and Montminy M. (2010). The CREB coactivator CRTC3 links catecholamine signaling to energy balance. Nature. 468(7326): 933-9.
  • Berdeaux, R., Goebel, N., Banaszynski, L., Takemori, H., Wandless, T., Shelton, G.D., and Montminy, M.  (2007).  SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nat. Med. 13(5): 597-603.
  • Canettieri, G., Koo, S.H., Berdeaux, R., Heredia, J., Hedrick, S., Zhang, X., Montminy, M. (2005). Dual role of the coactivator TORC2 in modulating hepatic glucose output and insulin signaling. Cell Metab. 2(5):331-8.
  • Berdeaux, R.L., Díaz, B., Kim, L., Martin, G.S. (2004). Active Rho is localized to podosomes induced by oncogenic Src and is required for their assembly and function. J. Cell Biol. 166(3):317-23.
  • Hofer, F., Berdeaux, R., Martin, G.S. (1998). Ras-independent activation of Ral by a Ca(2+)-dependent pathway. Curr. Biol. 8(14):839-42.