About

Joe Chakkalakal is an Associate Professor in Orthopaedic Surgery and Cell Biology at Duke University School of Medicine. He is a member of the Duke Cancer Institute and is involved in programs related to Cell and Molecular Biology, Developmental & Stem Cell Biology, and Genetics and Genomics. His research focuses on understanding cellular and molecular mechanisms, particularly in the context of cancer and regenerative biology, contributing to the advancement of knowledge in these fields.

Research topics

• Cell biology
• Biology
• Immunology
• Endocrinology
• Physiology
• Neuroscience

Selected publications

• Age‐Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics

  Aging Cell · 2026-01-01 · 2 citations

  articleOpen access

  Age-associated degeneration of neuromuscular junctions (NMJs) contributes to sarcopenia and motor function decline, yet the mechanisms that drive this dysfunction in aging remain poorly defined. Here, we demonstrate that postsynaptic mitochondria are significantly diminished in quantity in old-aged skeletal muscle, correlating with increased denervation and delayed reinnervation following nerve injury. Single-nucleus RNA sequencing before and after sciatic nerve crush from young and old-aged muscles further revealed that sub-synaptic myonuclei in old-aged muscle exhibit attenuated expression of mitochondrial gene programs, including oxidative phosphorylation, biogenesis, and import. To test whether these deficits are causal, we developed a muscle-specific CRISPR genome editing approach and targeted CHCHD2 and CHCHD10-two nuclear-encoded mitochondrial proteins that localize to the intermembrane space and interact with the mitochondrial contact site and cristae organizing system. CRISPR knockout of CHCHD2 and CHCHD10 in young muscle recapitulated old-aged muscle phenotypes, including mitochondrial disorganization, reduced ATP production, NMJ fragmentation, and delayed reinnervation. Transcriptional profiling of sub-synaptic myonuclei using single-nuclei RNA sequencing from CHCHD2 and CHCHD10 knockout muscles revealed impairments in activation of mitochondrial remodeling programs and elevated stress signatures when compared with controls. These findings establish a critical role for postsynaptic mitochondrial integrity in sustaining NMJ stability and regenerative capacity and identify CHCH domain-containing proteins as key regulators of postsynaptic mitochondrial function during aging and injury.

  PublisherDOI

• Specific non-myogenic mesenchymal cells contribute to rotator cuff tear myosteatosis and fibrosis revealing novel therapeutic options

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-14

  articleOpen access

  ABSTRACT The rotator cuff is a group of four muscles in the shoulder, which aid in movement and rotation of the upper arm. Rotator cuff tears (RCTs) within tendons of these muscles are common musculoskeletal injuries, often resulting in intramuscular fat, fibrosis, and muscle atrophy. Fatty infiltration specifically correlates with high rates of retear following repair. The cellular sources and molecular cues that cause these pathologies are unknown and therefore non-surgical cell/drug therapies for RCTs do not exist. Thus, we first sought to determine the cellular source(s) and molecular underpinnings of fatty atrophy and fibrosis associated with massive RCTs. Using a murine model of massive RCTs combined with lineage tracing, we demonstrate that muscle resident Pdgfra+ non-myogenic mesenchymal cells (NMMCs) are responsible for the fatty and fibrotic RCT pathologies. Utilizing sorted Pdgfra+ cells from rotator cuff muscles and “deep” single cell RNA-sequencing, we identified a specific Dpp4+ cell population associated with RCT-induced fibrosis, while Gfra1+ nerve-associated NMMCs are drivers of the RCT-induced intramuscular fat pathology. Finally, we demonstrate that RCT-induced fatty infiltration occurs at least partially via the loss of GDNF-GFRA1-RET signaling, since local treatment of murine RCTs with a small molecule RET agonist reduces development of the RCT-induced intramuscular fat.

  PublisherDOI

• Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis

  Nature Aging · 2025-06-30 · 10 citations

  articleOpen access

  Aging is characterized by a decline in the functionality and number of stem cells across the organism. In this study, we uncovered a mechanism by which systemic inflammation drives muscle stem cell (MuSC) aging through epigenetic erosion. We demonstrate that age-related inflammation decreases monomethylation of H4K20 in MuSCs, disrupting their quiescence and inducing ferroptosis, a form of iron-dependent cell death. Our findings show that inflammatory signals downregulate Kmt5a, the enzyme responsible for depositing H4K20me1, leading to the epigenetic silencing of anti-ferroptosis genes. This results in aberrant iron metabolism, increased reactive oxygen species levels and lipid peroxidation in aged MuSCs. Notably, long-term inhibition of systemic inflammation that is initiated at 12 months of age effectively prevents ferroptosis, preserves MuSC numbers and enhances muscle regeneration and functional recovery. These findings reveal an epigenetic switch that links chronic inflammation to MuSC aging and ferroptosis, offering potential therapeutic strategies for combating age-related muscle degeneration. Blanc et al. uncover how chronic inflammation triggers an epigenetic switch in aged muscle stem cells, leading to iron accumulation and cell death by ferroptosis—offering insights into muscle aging and potential paths for regenerative therapies.

  PublisherOA PDFDOI

• Contribution of vascular endothelium to the regeneration of neuromuscular junctions after degenerative injury to adult skeletal muscle

  The Journal of Physiology · 2024-10-01 · 1 citations

  articleOpen access1st authorCorresponding

  Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

  PublisherOA PDFDOI

• Satellite cells in the growth and maintenance of muscle

  Current topics in developmental biology/Current Topics in Developmental Biology · 2024-01-01 · 7 citations

  articleSenior authorCorresponding
  PublisherDOI

• Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

  Research Square · 2024-03-15

  preprintOpen access
  PublisherDOI

• Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

  Research Square · 2024-02-14 · 2 citations

  preprintOpen access
  PublisherOA PDFDOI

• PGC-1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII

  Molecular Cell · 2023-01-01 · 15 citations

  articleOpen access
  PublisherOA PDFDOI

• Endurance exercise attenuates juvenile irradiation-induced skeletal muscle functional decline and mitochondrial stress

  Skeletal Muscle · 2022-04-12 · 10 citations

  articleOpen accessSenior authorCorresponding

  Abstract Background Radiotherapy is commonly used to treat childhood cancers and can have adverse effects on muscle function, but the underlying mechanisms have yet to be fully elucidated. We hypothesized that endurance exercise following radiation treatment would improve skeletal muscle function. Methods We utilized the Small Animal Radiation Research Platform (SARRP) to irradiate juvenile male mice with a clinically relevant fractionated dose of 3× (every other day over 5 days) 8.2 Gy X-ray irradiation locally from the knee to footpad region of the right hindlimb. Mice were then singly housed for 1 month in cages equipped with either locked or free-spinning voluntary running wheels. Ex vivo muscle contractile function, RT-qPCR analyses, resting cytosolic and sarcoplasmic reticulum (SR) store Ca 2+ levels, mitochondrial reactive oxygen species levels (MitoSOX), and immunohistochemical and biochemical analyses of muscle samples were conducted to assess the muscle pathology and the relative therapeutic impact of voluntary wheel running (VWR). Results Irradiation reduced fast-twitch extensor digitorum longus (EDL) muscle-specific force by 27% compared to that of non-irradiated mice, while VWR post-irradiation improved muscle-specific force by 37%. Radiation treatment similarly reduced slow-twitch soleus muscle-specific force by 14% compared to that of non-irradiated mice, while VWR post-irradiation improved specific force by 18%. We assessed intracellular Ca 2+ regulation, oxidative stress, and mitochondrial homeostasis as potential mechanisms of radiation-induced pathology and exercise-mediated rescue. We found a significant reduction in resting cytosolic Ca 2+ concentration following irradiation in sedentary mice. Intriguingly, however, SR Ca 2+ store content was increased in myofibers from irradiated mice post-VWR compared to mice that remained sedentary. We observed a 73% elevation in the overall protein oxidization in muscle post-irradiation, while VWR reduced protein nitrosylation by 35% and mitochondrial reactive oxygen species (ROS) production by 50%. Finally, we found that VWR significantly increased the expression of PGC1α at both the transcript and protein levels, consistent with an exercise-dependent increase in mitochondrial biogenesis. Conclusions Juvenile irradiation stunted muscle development, disrupted proper Ca 2+ handling, damaged mitochondria, and increased oxidative and nitrosative stress, paralleling significant deficits in muscle force production. Exercise mitigated aberrant Ca 2+ handling, mitochondrial homeostasis, and increased oxidative and nitrosative stress in a manner that correlated with improved skeletal muscle function after radiation.

  PublisherOA PDFDOI

• Identification of distinct non-myogenic skeletal-muscle-resident mesenchymal cell populations

  Cell Reports · 2022-05-01 · 63 citations

  articleOpen access

  non-myogenic muscle-resident mesenchymal cell populations that fit within a bipartite differentiation trajectory from a common progenitor. One branch of the trajectory gives rise to two populations of immune-responsive mesenchymal cells with strong adipogenic potential and the capability to respond to acute and chronic muscle injury, whereas the alternative branch contains two cell populations with limited adipogenic capacity and inherent mineralizing capabilities; one of the populations displays a unique neuromuscular junction association and an ability to respond to nerve injury.

  PublisherOA PDFDOI

Recent grants

• Interrelationships between age-related skeletal muscle stem cell and NMJ decline

  NIH · $1.9M · 2015–2021

• Cellular Basis for Radiation induced acceleration of sarcopenia in juvenile cancer survivors

  NIH · $1.8M · 2017–2023

Frequent coauthors

• Bernard J. Jasmin

  University of Ottawa

  45 shared

• Robin N. Michel

  Concordia University

  29 shared

• Eva R. Chin

  Response Biomedical (Canada)

  20 shared

• Pedro Miura

  University of Nevada, Reno

  16 shared

• Nicole D. Paris

  15 shared

• John F. Bachman

  Jackson Laboratory

  14 shared

• Mark A. Stocksley

  University of Ottawa

  13 shared

• Lynn A. Megeney

  University of Ottawa

  12 shared