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Principal Investigator: Cory Dungan
Organization: BAYLOR UNIVERSITY
Fiscal Year: 2024
Award: $215,600
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Summary. Skeletal muscle mass and function are key determinants of an individual’s healthspan and
are tightly correlated with both physical and metabolic health. In cancer survivors, the loss of muscle mass that
occurs following cancer, termed cancer cachexia, is a major contributor to mortality, as well as reduced quality
of life during and after the disease. Unfortunately, one of the most extensively used treatments for cancer
patients, chemotherapy, is almost as bad as the cancer itself due the negative effects that chemotherapy has
on healthy cells. Chemotherapy treatments such as cisplatin, induce DNA damage, thereby compounding an
already deleterious process in healthy tissues and cells. Severe or unrepaired DNA-damage causes cell death
and tissue atrophy, in addition to being a major inducer of cellular senescence. Recent work by our lab has
linked an accumulation of senescent cells as a novel contributing factor to cisplatin-mediated loss of muscle
mass and function. In response to cisplatin, there is an accumulation of senescent cells in muscle, which is
correlated to a reduction in muscle fiber cross-sectional area. Considering senescent cells have been linked to
sarcopenia, removal of these senescent cells using senescent cell killing compounds, senolytics, could help
slow muscle loss during cisplatin treatment. Exercise training is the most effective way to increase skeletal
muscle mass, in addition to improving physical function and whole-body metabolism. Following chemotherapy
treatment, the response to exercise is attenuated (termed anabolic resistance), and individuals treated with
chemotherapy following surgery have a blunted response to exercise compared with surgery alone. Given that
elimination of senescent cells augments muscle growth and regeneration in old mice, senolytics could serve as
a novel therapeutic intervention to not only delay cisplatin-induced atrophy but also improve the response to
exercise training. Our central hypothesis is that cisplatin-treated mice receiving senolytics will experience less
atrophy and an augmented response to exercise when compared to controls. We will utilize the plant-based
flavonoids, fisetin and quercetin (F+Q), as our senolytic cocktail. In addition to their excellent senolytics
properties, F+Q exert many other beneficial effects, such as antioxidant and anti-inflammatory, and promoting
mitochondrial biogenesis. To address our hypothesis, we will pursue three specific aims: 1) delete senescent
cells in mice treated with F+Q to determine if cellular senescence mediates cisplatin-induced muscle atrophy,
2) examine senescent cells as contributors to anabolic resistance following progressive weighted wheel
running, and 3) characterize the cellular landscape and identify the molecular signature of muscle senescent
cells. We will utilize an age-appropriate mouse model to identify the therapeutic potential of senescent cells to
slow both the physical and metabolic aspects of chemotherapy-induced cachexia and anabolic resistance. If
our hypothesis is correct, the results from our proposed studies could influence the treatment of cachexia and
associated metabolic derangement, thereby creating new interventions and therapeutic strategies.
Terms: <2-Phenyl-Benzopyrans><2-Phenyl-Chromenes><Abscission><Address><Adjuvant><Affect><Age><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antioxidants><Area><Atrophic><Atrophy><Attenuated><Automobile Driving><Bio-Informatics><Biogenesis><Bioinformatics><Body Tissues><CDDP><Cachectic><Cachexia><Cancer Cachexia><Cancer Patient><Cancer Survivor><Cancer Treatment><Cancers><Cell Aging><Cell Body><Cell Death><Cell Senescence><Cell secretion><Cells><Cellular Aging><Cellular Secretion><Cellular Senescence><Chemotactic Cytokines><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Creativeness><Cysplatyna><DNA Damage><DNA Injury><Data><Dichlorodiammineplatinum><Differences between sexes><Differs between sexes><Disease><Disorder><Environment><Excision><Exercise><Exhibits><Extirpation><Face><Female><Fiber><Flavonoids><Fluorescence Activated Cell Sorting Fractionation><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><Gastrocnemius Muscle><Gene Expression><Generalized Growth><Growth><Health><Hindlimb><Homologous Chemotactic Cytokines><Hour><Human><IP injection><Individual><Insulin Resistance><Intercrines><Intermediary Metabolism><Intervention><Intervention Strategies><Intraperitoneal Injections><Label><Link><Literature><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular Fingerprinting><Molecular Profiling><Murine><Mus><Muscle><Muscle Atrophy><Muscle Fibers><Muscle Tissue><Muscle function><Muscular Atrophy><Myotubes><Natural regeneration><Normalcy><Normalities><Operative Procedures><Operative Surgical Procedures><Oral><Origin of Life><Peyrone's Chloride><Peyrone's Salt><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Physical Function><Physiologic><Physiological><Plants><Platinum Diamminodichloride><Population><Process><Property><Protein Biosynthesis><QOL><Quality of life><Quercetin><Regeneration><Removal><Replicative Senescence><Research Design><Resistance><Rhabdomyocyte><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Running><SIS cytokines><Sex Differences><Sexual differences><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Soleus><Soleus Muscle><Study Type><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Survivors><Testing><Therapeutic><Therapeutic Intervention><Tissue Growth><Tissues><Treatment Protocols><Treatment Regimen><Treatment Schedule><Voluntary Muscle><Work><aged mice><aged mouse><ages><anti-cancer therapy><attenuate><attenuates><cancer associated cachexia><cancer induced cachexia><cancer therapy><cancer-associated muscle wasting><cancer-directed therapy><cancer-induced muscle atrophy><cancer-induced muscle loss><cancer-induced muscle wasting><cancer-related cachexia><cell killing><chemoattractant cytokine><chemokine><chemotherapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><compare to control><comparison control><creativity><cytokine><driving><effective intervention><elderly mice><exercise training><experience><faces><facial><fisetin><gastrocnemius><global gene expression><global transcription profile><health-span><healthspan><healthy life span><improved><in vivo><indexing><insight><insulin resistant><insulin tolerance><intervention therapy><interventional strategy><life span><lifespan><male><malignancy><mid life><mid-life><middle age><middle aged><midlife><mitochondrial><molecular profile><molecular signature><mortality><mouse model><murine model><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle hypertrophy><muscle loss><muscle mass><muscle wasting><muscular><necrocytosis><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><normality><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><old mice><ontogeny><pharmaceutical><preservation><protein synthesis><regenerate><resection><resistant><response><sarcopenia><sarcopenic><scRNA-seq><sedentary><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><senescent cell><senolytics><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><study design><surgery><transcriptome><tumor-induced cachexia><tumor-induced muscle wasting>