Laboratory of Skeletal Muscle
and Stem Cell Biology
Joe V. Chakkalakal
Ph.D. 2006 University of Ottawa, Canada
Postdoctoral Training 2006-2009 Harvard University,
Molecular and Cellular Biology
Postdoctoral Training 2010-2013 Massachusetts General Hospital,
Center for Regenerative Medicine
Assistant Professor of Orthopaedics
Primary Appointment: Department of Orthopaedics
Center for Musculoskeletal Research
UR Stem Cell and Regenerative Medicine Institute
The Rochester Aging Research (RoAR) Center
Sarcopenia is the prolonged loss of skeletal muscle mass and function with age. A significant contributor to falls, frailty and loss in functional mobility, disabilities related to sarcopenia are a burgeoning cost to healthcare systems. Hence, the identification of factors that promote skeletal muscle maintenance is of critical importance. The progression of sarcopenia correlates with reductions in the number and function of resident stem cells of skeletal muscle, satellite cells. However, the relevance of this decline toward age-related skeletal muscle dysfunction and the identity of factors that maintain the integrity of the satellite cell pool at homeostasis are ambiguous. To address these queries, my laboratory utilizes targeted mouse genetics and injury models to determine how molecules of interest affect satellite cell fate and skeletal muscle regenerative outcomes. We hope insights gained from these studies can be exploited to promote skeletal muscle growth and maintenance in a variety of contexts including aging.
Satellite cell maintenance and skeletal muscle regeneration
Age-related alterations in FGF, Notch, Wnt and TGFβ/BMP signaling can profoundly influence skeletal muscle regenerative capacity and satellite cell maintenance. We are currently using mouse genetics to decipher modes of interactions between some of these signaling cascades in the regulation of satellite cell fate at homeostasis and during regeneration.
Neuromuscular disruption, sex hormone deprivation and satellite cell fate
Aging is associated with significant declines in circulating sex hormone levels and disruptions in neuromuscular maintenance, both mediators of skeletal muscle loss and dysfunction. My laboratory employs mouse genetics, established models of hormone deprivation and neuromuscular disruption to determine how these insults affect satellite cell maintenance and fate.
Chakkalakal JV, Christensen J, Xiang W, Tierney MT, Boscolo FS, Sacco A, Brack AS. Early forming label-retaining muscle stem cells require p27kip1 for maintenance of the primitive state. Development. 2014 Apr;141(8):1649-59. doi: 10.1242/dev.100842.
Chakkalakal JV, Jones KM, Basson A, Brack AS. (2012) The aged niche disrupts muscle stem cell quiesence. Nature. 490 (7420): 355-60.
Chakkalakal JV, Kuang S, Buffelli M, Lichtman JW, Sanes JR. (2012) Mouse transgenic lines that selectively label type I, type IIA and type IIX+IIB skeletal muscle fibers. Genesis. 50(1);50-58.
Chakkalakal JV, Nishimune H, Ruas J, Spiegelman BM, Sanes JR. (2010) Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motor neurons. Development. 137: 3489-3499. (Recommended by Faculty of Biology 1000).
Miura P, Chakkalakal JV, Boudreault L, Bélanger G, Hébert RL, Renaud JM, Jasmin BJ. (2009) Pharmacological activation of PPARbeta/delta stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature mdx mice. Hum Mol Genet. 18:4640-4649.
Chakkalakal JV, Miura P, Bélanger G, Michel RN, Jasmin BJ. (2008) Modulation of utrophin A mRNA stability in fast versus slow muscles via an AU-rich element and calcineurin signaling. Nucleic Acids Res. 36(3):826-838.
Chakkalakal JV, Michel SA, Chin ER, Michel RN, Jasmin BJ. (2006) Targeted inhibition of Ca2+ /calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle. Hum Mol Genet. 15(9):1423-1435.
Miura P, Thompson J, Chakkalakal JV, Holcik M, Jasmin BJ. (2005) The Utrophin A 5’UTR Confers IRES-Mediated Translational Control During Regeneration of Skeletal Muscle Fibers. J. Biol. Chem 280(38):32997-3005.
Chakkalakal JV, Angus LM, Méjat A, Bélanger G, Megeney LA, Schaeffer LA, Michel RN, Jasmin BJ. (2005) Calcineurin/NFAT Signalling, Together with GABP and PGC-1alpha, Drives Synaptic Gene Expression at the Neuromuscular Junction. Am J Cell Physiol 289(4):C908-C917
Chakkalakal JV, Stocksley MA, Bradford A, Miura P, De Repentigny Y, Kothary R, Jasmin BJ. (2005) A 1.3 kb Promoter Fragment Confers Spatial and Temporal Expression of Utrophin A mRNA in Mouse Skeletal Muscle Fibers. Neuromuscular Disorders. 15(6):437-449.
St-Pierre SJ, Chakkalakal JV, Kolodziejczyk SM, Knudson JC, Jasmin BJ, Megeney LA. (2004) Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway. FASEB J. 18(15):1937-1939.
Chakkalakal JV, Harrison MA, Carbonetto S, Chin E, Michel RN, Jasmin BJ. (2004) Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice. Hum Mol Genet. 13(4):379-388.
Chakkalakal JV, Stocksley MA, Harrison MA, Angus LM, Deschenes-Furry J, St-Pierre S, Megeney LA, Chin ER, Michel RN, Jasmin BJ. (2003) Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling. Proc Natl Acad Sci U S A. 100(13):7791-7796.
Department of Defense: W81XWH-14-1-0454
"Cellular Basis for ADT-induced Acceleration of Sarcopenia"
September 30, 2014 - September 29, 2017
Chakkalakal JV and Brack AS (2012) Extrinsic Regulation of Satellite Cell Function and Muscle Regeneration Capacity during Aging. Stem Cell Res Ther. S11:001. doi: 10.4172/2157-7633.S11-001.
Chakkalakal JV, Thompson J, Parks RJ, Jasmin BJ. (2005) Molecular, cellular, and pharmacological therapies for Duchenne/Becker muscular dystrophies. FASEB J. 19(8):880-891.
Chakkalakal JV, Jasmin BJ. (2003) Localizing synaptic mRNAs at the neuromuscular junction: it takes more than transcription. Bioessays. 25(1):25-31.
Graduate Program Affiliation
Joe V. Chakkalakal, PhD
University of Rochester
601 Elmwood Ave., Box 665
Rochester, NY 14642
Office: SMD 1-8566D
(585) 275-1121 (fax)
|Alanna KloseLab Tech III|