Laboratory of Skeletal Muscle

and Stem Cell Biology

Joe V. Chakkalakal

Joe Chakkalakal PhD
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 Affilidation: Center for Musculoskeletal Research

Research Overview

Satellite cells are a population of resident stem cells that serve as a renewable source of progenitors for the growth and regeneration of skeletal muscle. Recently, we identified age-related signals from the principal niche cell (the muscle fiber) that compromised the integrity of the satellite cell pool. The extent and stability of these age-related changes have yet to be fully explored. To address these issues, we utilize targeted mouse genetics to specifically manipulate signals of interest in satellite cells or niche components. In conjunction, we employ cell culture systems and transplant procedures to assess the fate potentials of satellite cell populations. We routinely utilize quantitative RNA analysis from FACs purified populations of satellite cells and single muscle fibers to characterize molecular signatures of altered function and signaling. These assays are complemented by immunocytochemical, histochemical and biochemical assays to visualize skeletal muscle morphology, patterns of gene expression and the activity of molecules of interest. Finally, we couple our cellular and molecular based assays to relevant readouts of skeletal muscle regenerative outcomes. Ultimately, we aim to decipher at a molecular level satellite cell character in a variety of contexts. We hope to exploit such insight to promote optimal skeletal muscle growth and maintenance in diverse settings.

Projects

 

Signaling and Skeletal Muscle Regeneration

 

Signaling and skeletal muscle regeneration

Our lab and others have recently shown 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 and defined culture systems to decipher molecular modes of interactions between these signaling cascades that affect satellite cell fate during regeneration.

Skeletal Muscle Heterogeneity

Muscle Heterogeneity
Most skeletal muscles are composed of a heterogeneous mixture of functionally diverse muscle fibers that differ in contractile and metabolic capability. Fiber type transitions and associated modulations in strength are observed with age and disease. We are currently examining the cellular and molecular mechanisms responsible for fiber type transitions in various conditions. Additionally, we are studying the cellular and molecular basis for the establishment and maintenance of skeletal muscle fiber heterogeneity.

 

Selected Publications

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.

Selected Reviews

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

Contact

Joe V. Chakkalakal, PhD
University of Rochester
601 Elmwood Ave., Box 665
Rochester, NY 14642
Office: SMD 1-8566D
(585) 273-5631
(585) 275-1121 (fax)
joe_chakkalakal@
urmc.rochester.edu

 

Lab Members

 

Debamita Chatterjee, PhD

Debamita Chatterjee, PhD

Alanna Klose Alanna KloseLab Tech III
Andrew Soroka

Andrew Soroka

MD/PhD Student

Wenxuan Liu

Wenxuan Liu

PhD Student