We study the cellular and molecular mechanisms underlying neuromuscular development, regeneration, and aging, emphasizing understanding stem and progenitor cell fate, function, and niche biology. We are affiliated with the Departments of Orthopaedic Surgery and Cell Biology as part of the Duke Orthopaedic Cellular, Developmental, and Genome Laboratories within the Duke University School of Medicine.

Aging-related declines in neuromuscular regeneration:

Aging is associated with significant deficiencies in skeletal muscle regeneration. We believe the inhibition of regenerated aged myofiber recovery coupled with interstitial pathological infiltrate and fibrosis is due to impairments in the reconstitution of the neuromuscular junction (NMJ). The synapse between a motor axon terminal and myofiber is located on this specialized site. Current studies include examining the cellular basis for restoring NMJs after injury. We are also pursuing mechanisms such as manipulating relevant stem and progenitor cell populations that may alter NMJ reconstitution after injury and how they impact myofiber recovery, interstitial pathological infiltrate, and fibrosis.

Postnatal neuromuscular growth and the consequences of pediatric cancer therapies:

Neuromuscular impairments are among the aging-related phenotypes observed earlier in pediatric cancer survivors. Early adolescence to adulthood is a significant skeletal muscle growth period with active stem and progenitor cell activity sensitive to pediatric cancer therapies such as radiation and chemotherapy. Current studies examine how modulations in the cellular composition of skeletal muscle, the fate of stem and progenitor cell populations, and alterations of the muscle stem cell niche from early adolescence to adulthood impact healthy aging. We are also pursuing strategies to alleviate pediatric cancer therapies' near and long-term impact during this dynamic stage of neuromuscular growth.

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Grants

• Engineering a Human Skeletal Muscle Tissue Model of LGMD2B ResearchCo Investigator · Awarded by National Institutes of Health · 2023 - 2028
   
• Training Program in Developmental and Stem Cell Biology Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2001 - 2027
   
• Cell and Molecular Biology Training Program Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2021 - 2026
   
• Understanding and engineering the relationship of muscle stem cells with the neuromuscular junction in agingResearchPrincipal Investigator · Awarded by the University of Michigan · 2023 - 2024
   
• Cellular Basis for Radiation-induced acceleration of sarcopenia in juvenile cancer survivors ResearchPrincipal Investigator · Awarded by National Institutes of Health · 2022 - 2023

Fellowships, Gifts, and Supported Research

• Cellular Basis for Radiation-induced acceleration of Sarcopenia in juvenile cancer survivors · August 1, 2017 - July 31, 2022 National Cancer Institute (Rockville, US)
• Interrelationships between age-related skeletal muscle stem cell and NMJ decline · September 30, 2015 - May 31, 2020 National Institute on Aging (Bethesda, US)
• The Establishment of Motor Unit Homogeneity during Development and after Axon Regeneration · October 1, 2006 - September 30, 2009 Canadian Institutes of Health Research (Ottawa, CA)
• Transcriptional and post-transcriptional regulation of utrophin expression in fast versus slow skeletal muscles · May 1, 2003 - April 30, 2006 Canadian Institutes of Health Research (Ottawa, CA)
• Cellular Basis for ADT-Induced Acceleration of Sarcopenia · September 1, 2014 - July 31, 2017 Congressionally Directed Medical Research Programs (Fort Detrick, US)

Current Members:

• Sabrina DeStefano, Graduate Student
• Koji Ishikawa, Postdoctoral Fellow
• Anthony Mirando, Research Analyst II
• Ashley Ontiri, Research Technician
• Danny Panken, Graduate Student
• Vedant Patel, Undergraduate Student
• Cathy Yang, Undergraduate Student

Alumni Members:

• Elena Torres-Ponce, Research Technician (2022-2023)
• Alanna Klose (2013-2017) (Research Technician)
• Wenxuan Liu (2013-2017) (PhD Genetics 2017)
• Andrew Soroka (2014-2016) (MD, MSc Pathology 2015)
• Nicole Paris (2015-2021) (Postdoctoral Fellow/Staff Scientist)
• Melissa Schmalz (2016-2017) (Research Technician)
• John Bachman (2017-2021) (PhD Pathology 2021)
• Romeo Blanc (2017-2021) (Postdoctoral Fellow)
• Thomas O’Connor (2018-2020) (MSc Genetics 2020)
• Jacob Kallenbach (2018-2021) (PhD Biomedical Engineering 2021)
• Esraa Furati (2018-2022) (Graduate Student in Pharmacology and Physiology)
• Sophia Forman (2015-2017) (Undergraduate Student)
• Amanda Mitchell (2018) (Summer Scholars Undergraduate Student)
• Ketsia Seide (2019) (Summer Scholars Undergraduate Student)
• Haley Orciuoli (2021) (Undergraduate Student)
• Ava Schwartz (2021) (Undergraduate Student)

Selected Publications

• Chakkalakal JV, Stocksley MA, Harrison MA, Angus LM, Deschenes-Furry J, St-Pierre S, Megeney LA, Chin ER, Michel RN, Jasmin BJ. 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. 2003 Jun 24;100(13):7791-6. doi: 10.1073/pnas.0932671100. PMID: 12808150
   
• Chakkalakal JV, Nishimune H, Ruas JL, Spiegelman BM, Sanes JR. Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motoneurons. Development. 2010 Oct;137(20):3489-99. doi: 10.1242/dev.053348. PMID: 20843861
   
• Chakkalakal JV, Jones KM, Basson MA, Brack AS. The aged niche disrupts muscle stem cell quiescence. Nature. 2012 Oct 18;490(7420):355-60. doi: 10.1038/nature11438. PMID: 23023126
   
• Chakkalakal JV, Christensen J, Xiang W, Tierney MT, Boscolo FS, Sacco A, Brack AS. Early forming label-retaining muscle stem cells require p27kip1 to maintain the primitive state. Development. 2014 Apr;141(8):1649-59. doi: 10.1242/dev.100842. PMID: 24715455
   
• Liu W, Wei-LaPierre L, Klose A, Dirksen RT, Chakkalakal JV. Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions. Elife. 2015 Aug 27;4. doi: 10.7554/eLife.09221. PMID: 26312504
   
• Liu W, Klose A, Forman S, Paris ND, Wei-LaPierre L, Cortés-Lopéz M, Tan A, Flaherty M, Miura P, Dirksen RT, Chakkalakal JV. Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration. Elife. 2017 Jun 6;6. doi: 10.7554/eLife.26464. PMID: 28583253
   
• Bachman JF, Klose A, Liu W, Paris ND, Blanc RS, Schmalz M, Knapp E, Chakkalakal JV. Prepubertal skeletal muscle growth requires Pax7-expressing satellite cell-derived myonuclear contribution. Development. 2018 Oct 25;145(20). doi: 10.1242/dev.167197. PMID: 30305290
   
• Blanc RS, Kallenbach JG, Bachman JF, Mitchell A, Paris ND, Chakkalakal JV. Inhibition of inflammatory CCR2 signaling promotes aged muscle regeneration and strength recovery after injury. Nat Commun. 2020 Aug 20;11(1):4167. doi: 10.1038/s41467-020-17620-8. PMID: 32820177
   
• Kallenbach JG, Bachman JF, Paris ND, Blanc RS, O’Connor T, Furati E, Williams JP, Chakkalakal JV. Muscle-specific functional deficits and lifelong fibrosis in response to paediatric radiotherapy and tumour elimination. J Cachexia Sarcopenia Muscle. 2022 Feb;13(1):296-310. doi: 10.1002/jcsm.12902. Epub 2022 Jan 8. PMID: 34997696

• Small animal models of degenerative muscle injury, longitudinal physiology, and syngeneic tumor growth/treatment.
• Flow cytometry applications.
• Large-scale single cell and spatial analysis.

If you are interested in joining the Chakkalakal Lab team, contact joe.chakkalakal@duke.edu.