Scholars@Duke
Joe Chakkalakal

Joe Chakkalakal

Associate Professor in Orthopaedic Surgery
Orthopaedic Surgery

Selected Publications

Satellite cells in the growth and maintenance of muscle.

Chapter · 2024 Embryonic skeletal muscle growth is contingent upon a population of somite derived satellite cells, however, the contribution of these cells to early postnatal skeletal muscle growth remains relatively high. As prepubertal postnatal development proceeds, t ... Full text Link to item Cite

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

Journal Article Mol Cell · January 19, 2023 PGC-1α is well established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1α activates gene transcription are incompletely understood. Here, we report that PGC-1α serves as a sca ... Full text Link to item Cite

Exercise attenuates juvenile irradiation-induced skeletal muscle decline by improving calcium handling and decreasing mitochondrial stress

Other The Journal of general physiology · September 5, 2022 Proper skeletal muscle development, maintenance, and function is necessary for movement. Decline in muscle function with age and disease is directly associated with a diminished quality of life. Radiation therapy is commonly used to treat certain forms of ... Full text Open Access Cite

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

Journal Article Cell Rep · May 10, 2022 Mesenchymal progenitors of the lateral plate mesoderm give rise to various cell fates within limbs, including a heterogeneous group of muscle-resident mesenchymal cells. Often described as fibro-adipogenic progenitors, these cells are key players in muscle ... Full text Open Access Link to item Cite

Insights into muscle stem cell dynamics during postnatal development.

Journal Article FEBS J · May 2022 During development, resident stem cell populations contribute to the growth and maturation of tissue and organs. In skeletal muscle, muscle stem cells, or satellite cells (SCs), are responsible for the maturation of postnatal myofibers. However, the role S ... Full text Link to item Cite

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

Journal Article Skelet Muscle · April 12, 2022 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 ... Full text Link to item Cite

Muscle-specific functional deficits and lifelong fibrosis in response to paediatric radiotherapy and tumour elimination.

Journal Article J Cachexia Sarcopenia Muscle · February 2022 BACKGROUND: As paediatric cancer survivors are living into adulthood, they suffer from the age-related, accelerated decline of functional skeletal muscle tissue, termed sarcopenia. With ionizing radiation (radiotherapy) at the core of paediatric cancer the ... Full text Link to item Cite

Murine muscle stem cell response to perturbations of the neuromuscular junction are attenuated with aging.

Journal Article Elife · July 29, 2021 During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function impacting mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells o ... Full text Link to item Cite

Increased myocellular lipid and IGFBP-3 expression in a pre-clinical model of pancreatic cancer-related skeletal muscle wasting.

Journal Article J Cachexia Sarcopenia Muscle · June 2021 BACKGROUND: Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinom ... Full text Link to item Cite

Radiation-Induced Damage to Prepubertal Pax7+ Skeletal Muscle Stem Cells Drives Lifelong Deficits in Myofiber Size and Nuclear Number.

Journal Article iScience · November 20, 2020 During prepubertal development, muscle stem cells (satellite cells, SCs) actively contribute to myofiber growth. Because some SCs are active during this time, they may be particularly susceptible to damage. Using a Small Animal Radiation Research Platform ... Full text Link to item Cite

Chemoradiation impairs myofiber hypertrophic growth in a pediatric tumor model.

Journal Article Sci Rep · November 11, 2020 Pediatric cancer treatment often involves chemotherapy and radiation, where off-target effects can include skeletal muscle decline. The effect of such treatments on juvenile skeletal muscle growth has yet to be investigated. We employed a small animal irra ... Full text Link to item Cite

Inhibition of inflammatory CCR2 signaling promotes aged muscle regeneration and strength recovery after injury.

Journal Article Nat Commun · August 20, 2020 Muscle regeneration depends on a robust albeit transient inflammatory response. Persistent inflammation is a feature of age-related regenerative deficits, yet the underlying mechanisms are poorly understood. Here, we find inflammatory-related CC-chemokine- ... Full text Link to item Cite

TNF Receptor-Associated Factor 6 Mediates TNFα-Induced Skeletal Muscle Atrophy in Mice During Aging.

Journal Article J Bone Miner Res · August 2020 During aging, muscle mass decreases, leading to sarcopenia, associated with low-level chronic inflammation (inflammaging), which induces sarcopenia by promoting proteolysis of muscle fibers and inhibiting their regeneration. Patients with a variety of path ... Full text Link to item Cite

Prostate tumor-derived GDF11 accelerates androgen deprivation therapy-induced sarcopenia.

Journal Article JCI Insight · March 26, 2020 Most prostate cancers depend on androgens for growth, and therefore, the mainstay treatment for advanced, recurrent, or metastatic prostate cancer is androgen deprivation therapy (ADT). A prominent side effect in patients receiving ADT is an obese frailty ... Full text Link to item Cite

Selective Sexual Dimorphisms in Musculoskeletal and Cardiopulmonary Pathologic Manifestations and Mortality Incidence in the Tumor Necrosis Factor-Transgenic Mouse Model of Rheumatoid Arthritis.

Journal Article Arthritis Rheumatol · September 2019 OBJECTIVE: To examine and quantify the sexual dimorphism in pathologic features manifested in the musculoskeletal and cardiopulmonary systems and incidence of mortality in the tumor necrosis factor-transgenic (TNF-Tg; Tg3647 strain) mouse model of inflamma ... Full text Link to item Cite

4-Aminopyridine attenuates muscle atrophy after sciatic nerve crush injury in mice.

Journal Article Muscle Nerve · August 2019 INTRODUCTION: We recently demonstrated the beneficial effects of 4-aminopyridine (4-AP), a potassium channel blocker, in enhancing remyelination and recovery of nerve conduction velocity and motor function after sciatic nerve crush injury in mice. Although ... Full text Link to item Cite

Prepubertal skeletal muscle growth requires Pax7-expressing satellite cell-derived myonuclear contribution.

Journal Article Development · October 25, 2018 The functional role of Pax7-expressing satellite cells (SCs) in postnatal skeletal muscle development beyond weaning remains obscure. Therefore, the relevance of SCs during prepubertal growth, a period after weaning but prior to the onset of puberty, has n ... Full text Link to item Cite

Castration induces satellite cell activation that contributes to skeletal muscle maintenance

Journal Article JCSM Rapid Communications · January 2018 AbstractAimsSarcopenia, the age‐related loss of skeletal muscle, is a side effect of androgen deprivation therapy (ADT) for prostate cancer patients. Resident stem cells of skeletal muscle ... Full text Cite

The Composition, Development, and Regeneration of Neuromuscular Junctions.

Chapter · 2018 The neuromuscular junction (NMJ) is the specialized site that connects the terminal of a motor neuron axon to skeletal muscle. As a synapse NMJ integrity is essential for transducing motor neuron signals that initiate skeletal muscle contraction. Many dise ... Full text Link to item Cite

Research priorities in cancer cachexia: The University of Rochester Cancer Center NCI Community Oncology Research Program Research Base Symposium on Cancer Cachexia and Sarcopenia.

Journal Article Curr Opin Support Palliat Care · December 2017 PURPOSE OF REVIEW: Cancer cachexia remains understudied and there are no standard treatments available despite the publication of an international consensus definition and the completion of several large phase III intervention trials in the past 6 years. I ... Full text Link to item Cite

Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration.

Journal Article Elife · June 6, 2017 Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age-associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to ... Full text Link to item Cite

Smad4 restricts differentiation to promote expansion of satellite cell derived progenitors during skeletal muscle regeneration.

Journal Article Elife · November 18, 2016 Skeletal muscle regenerative potential declines with age, in part due to deficiencies in resident stem cells (satellite cells, SCs) and derived myogenic progenitors (MPs); however, the factors responsible for this decline remain obscure. TGFβ superfamily s ... Full text Link to item Cite

TGFβ Superfamily Members Mediate Androgen Deprivation Therapy-Induced Obese Frailty in Male Mice.

Journal Article Endocrinology · November 2016 First line treatment for recurrent and metastatic prostate cancer is androgen deprivation therapy (ADT). Use of ADT has been increasing in frequency and duration, such that side effects increasingly impact patient quality of life. One of the most significa ... Full text Link to item Cite

Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions.

Journal Article Elife · August 27, 2015 Skeletal muscle maintenance depends on motor innervation at neuromuscular junctions (NMJs). Multiple mechanisms contribute to NMJ repair and maintenance; however muscle stem cells (satellite cells, SCs), are deemed to have little impact on these processes. ... Full text Link to item Cite

Early forming label-retaining muscle stem cells require p27kip1 for maintenance of the primitive state.

Journal Article Development · April 2014 Across different niches, subsets of highly functional stem cells are maintained in a relatively dormant rather than proliferative state. Our understanding of proliferative dynamics in tissue-specific stem cells during conditions of increased tissue turnove ... Full text Link to item Cite

The aged niche disrupts muscle stem cell quiescence.

Journal Article Nature · October 18, 2012 The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that t ... Full text Link to item Cite

Extrinsic Regulation of Satellite Cell Function and Muscle Regeneration Capacity during Aging.

Journal Article J Stem Cell Res Ther · September 26, 2012 Optimal regeneration of skeletal muscle in response to injury requires the contribution of tissue resident stem cells termed satellite cells. Normally residing at the interface between the muscle fiber and overlying basal lamina it is generally understood ... Full text Link to item Cite

Mouse transgenic lines that selectively label Type I, Type IIA, and Types IIX+B skeletal muscle fibers.

Journal Article Genesis · January 2012 Skeletal muscle fibers vary in contractile and metabolic properties. Four main fiber types are present in mammalian trunk and limb muscles; they are called I, IIA, IIX, and IIB, ranging from slowest- to fastest-contracting. Individual muscles contain stere ... Full text Link to item Cite

Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motoneurons.

Journal Article Development · October 2010 Mammalian limb and trunk skeletal muscles are composed of muscle fibers that differ in contractile and molecular properties. They are commonly divided into four categories according to the myosin heavy chain that they express: I, IIA, IIX and IIB, ranging ... Full text Link to item Cite

Pharmacological activation of PPARbeta/delta stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature mdx mice.

Journal Article Hum Mol Genet · December 1, 2009 A therapeutic strategy to treat Duchenne muscular dystrophy (DMD) involves identifying compounds that can elevate utrophin A expression in muscle fibers of affected patients. The dystrophin homologue utrophin A can functionally substitute for dystrophin wh ... Full text Link to item Cite

Modulation of utrophin A mRNA stability in fast versus slow muscles via an AU-rich element and calcineurin signaling.

Journal Article Nucleic Acids Res · February 2008 We examined the role of post-transcriptional mechanisms in controlling utrophin A mRNA expression in slow versus fast skeletal muscles. First, we determined that the half-life of utrophin A mRNA is significantly shorter in the presence of proteins isolated ... Full text Link to item Cite

Ca2+/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression.

Journal Article Appl Physiol Nutr Metab · October 2007 Ca2+ signalling plays an important role in excitation-contraction coupling and the resultant force output of skeletal muscle. It is also known to play a crucial role in modulating both short- and long-term muscle cellular phenotypic adaptations associated ... Full text Link to item Cite

Targeted inhibition of Ca2+ /calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle.

Journal Article Hum Mol Genet · May 1, 2006 In this study, we crossbred mdx mice with transgenic mice expressing a small peptide inhibitor for calmodulin (CaM), known as the CaM-binding protein (CaMBP), driven by the slow fiber-specific troponin I slow promoter. This strategy allowed us to determine ... Full text Link to item Cite

Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction.

Journal Article Am J Physiol Cell Physiol · October 2005 We examined whether calcineurin-NFAT (nuclear factors of activated T cells) signaling plays a role in specifically directing the expression of utrophin in the synaptic compartment of muscle fibers. Immunofluorescence experiments revealed the accumulation o ... Full text Link to item Cite

Regulation of utrophin in transgenic mice.

Journal Article Neuromuscul Disord · October 2005 Full text Link to item Cite

Reply to Davies

Journal Article Neuromuscular Disorders · October 2005 Full text Cite

The utrophin A 5'-untranslated region confers internal ribosome entry site-mediated translational control during regeneration of skeletal muscle fibers.

Journal Article J Biol Chem · September 23, 2005 Utrophin up-regulation in muscle fibers of Duchenne muscular dystrophy patients represents a potential therapeutic strategy. It is thus important to delineate the regulatory events presiding over utrophin in muscle in attempts to develop pharmacological in ... Full text Link to item Cite

A 1.3 kb promoter fragment confers spatial and temporal expression of utrophin A mRNA in mouse skeletal muscle fibers.

Journal Article Neuromuscul Disord · June 2005 Upregulation of utrophin in muscle is currently being examined as a potential therapy for Duchenne muscular dystrophy patients. In this context, we generated transgenic mice harboring a 1.3 kb human utrophin A promoter fragment driving expression of the la ... Full text Link to item Cite

Molecular, cellular, and pharmacological therapies for Duchenne/Becker muscular dystrophies.

Journal Article FASEB J · June 2005 Although the molecular defect causing Duchenne/Becker muscular dystrophy (DMD/BMD) was identified nearly 20 years ago, the development of effective therapeutic strategies has nonetheless remained a daunting challenge. Over the years, a variety of different ... Full text Link to item Cite

Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway.

Journal Article FASEB J · December 2004 Duchenne muscular dystrophy (DMD) is a progressive and ultimately fatal skeletal muscle disease. Currently, the most effective therapy is the administration of a subclass of glucocorticoids, most notably deflazacort. Although deflazacort treatment can atte ... Full text Link to item Cite

Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice.

Journal Article Hum Mol Genet · February 15, 2004 Utrophin has been studied extensively in recent years in an effort to find a cure for Duchenne muscular dystrophy. In this context, we previously showed that mice expressing enhanced muscle calcineurin activity (CnA*) displayed elevated levels of utrophin ... Full text Link to item Cite

Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling.

Journal Article Proc Natl Acad Sci U S A · June 24, 2003 Utrophin levels have recently been shown to be more abundant in slow vs. fast muscles, but the nature of the molecular events underlying this difference remains to be fully elucidated. Here, we determined whether this difference is due to the expression of ... Full text Link to item Cite

Localizing synaptic mRNAs at the neuromuscular junction: it takes more than transcription.

Journal Article Bioessays · January 2003 The neuromuscular junction has been used for several decades as an excellent model system to examine the cellular and molecular events involved in the formation and maintenance of a differentiated chemical synapse. In this context, several laboratories hav ... Full text Link to item Cite

Multiple regulatory events controlling the expression and localization of utrophin in skeletal muscle fibers: insights into a therapeutic strategy for Duchenne muscular dystrophy.

Journal Article J Physiol Paris · 2002 Duchenne muscular dystrophy (DMD) is the most prevalent inherited muscle disease and results from mutations/deletions in the X-linked dystrophin gene. Although several approaches have been envisaged to counteract the effects of this progressive disease, th ... Full text Link to item Cite

Increased expression of utrophin in a slow vs. a fast muscle involves posttranscriptional events.

Journal Article Am J Physiol Cell Physiol · October 2001 In addition to showing differences in the levels of contractile proteins and metabolic enzymes, fast and slow muscles also differ in their expression profile of structural and synaptic proteins. Because utrophin is a structural protein expressed at the neu ... Full text Link to item Cite