We focus on the cellular and molecular mechanisms driving skeletal muscle growth and adaptation, particularly stem and progenitor cell fate, cell-niche interactions, and their long-term health implications. Our research is housed within the Duke University School of Medicine, Department of Orthopaedic Surgery, Cellular, Developmental, and Genome Laboratories. We are also affiliated with the Duke Cancer Institute and collaborate with the Department of Cell Biology and several Duke University programs, including Cell and Molecular Biology, Genetics and Genomics, and Development and Stem Cell Biology.

Cellular Basis of Skeletal Muscle Growth, Adaptation, and Long-Term Health

Childhood represents a critical period for skeletal muscle growth. Deficits in muscle mass during adolescence are linked to increased risks of metabolic syndrome, cardiovascular disease, and aging-related disorders such as osteoporosis and sarcopenia. Our research has shown that stem and progenitor cell activity plays a key role in pediatric muscle growth, particularly in cases where the child is vulnerable to stressors, including cancer treatments such as radiation and chemotherapy.

Our current studies focus on:

1. Genomics: Identifying the cellular mechanisms underlying persistent stress and adaptation in skeletal muscle following pediatric insults.
2. Mouse Genetic Models: Investigating how pediatric insults induce cellular adaptations in skeletal muscle and their long-term health consequences.
3. Physiology and Exercise: Evaluating the impact of interventions during the pediatric period on skeletal muscle function, adaptation, and long-term health outcomes.

Grants

• Role of GDF15 in Genotoxic Stress-Induced Regulation of Skeletal Muscle Fibro-Adipogenic Progenitor Activity, Fibrosis, Growth, and Regeneration
  J. Chakkalakal ⸱ National Cancer Institute ⸱ 2024 - 2029

• Genetic and Therapeutic Approaches to Alleviate the Pathology of Massive Rotator Cuff Tears
  M.J. Hilton, +1 collaborator ⸱ National Institutes of Health ⸱ 2024 - 2026

• Understanding and Engineering the Relationship of Muscle Stem Cells with the Neuromuscular Junction in Aging
  C.A. Aguilar ⸱ University of Michigan ⸱ 2023 - 2026

• Cellular Basis for Radiation-Induced Acceleration of Sarcopenia in Juvenile Cancer Survivors
  J. Chakkalakal ⸱ National Institutes of Health ⸱ 2017 - 2023

• Chondrocyte DNA Double-Strand Breaks in the Pathogenesis of Osteoarthritis
  J. Jonason ⸱ University of Rochester ⸱ 2022 - 2025

• Engineering Heterocellular Human Skeletal Muscle Tissues to Recreate and Study Native Stem Cell Niche Function
  N. Bursac, +3 collaborators ⸱ National Institutes of Health ⸱ 2024 - 2029

• Engineering a Human Skeletal Muscle Tissue Model of LGMD2B
  N. Bursac, +3 collaborators ⸱ National Institutes of Health ⸱ 2023 - 2028

• Notch Signaling in Non-Myogenic Mesenchymal Cells Regulates Muscle Development
  M.J. Hilton, +1 collaborator ⸱ National Institutes of Health ⸱ 2020 - 2023

• Training Program in Developmental and Stem Cell Biology
  D.L. Silver, +60 collaborators ⸱ National Institutes of Health ⸱ 2001 - 2027

• Cell and Molecular Biology Training Program
  M.S. Boyce, +127 collaborators ⸱ National Institutes of Health ⸱ 2021 - 2026

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.