A5078070376- Muscle Physiology and Disorders
- Genetics, Aging, and Longevity in Model Organisms
- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Adipose Tissue and Metabolism
- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Developmental Biology and Gene Regulation
- Endoplasmic Reticulum Stress and Disease
- Neurobiology and Insect Physiology Research
- Exercise and Physiological Responses
- Hippo pathway signaling and YAP/TAZ
- Invertebrate Immune Response Mechanisms
- Heat shock proteins research
- Animal Genetics and Reproduction
- Hearing, Cochlea, Tinnitus, Genetics
- Wnt/β-catenin signaling in development and cancer
- Genetics and Physical Performance
- Spaceflight effects on biology
- CRISPR and Genetic Engineering
- Viral Infectious Diseases and Gene Expression in Insects
- Skin and Cellular Biology Research
- Connexins and lens biology
- Plant Reproductive Biology
- GDF15 and Related Biomarkers
St. Jude Children's Research Hospital
2014-2025
Harvard University
2009-2014
Max Planck Institute of Molecular Cell Biology and Genetics
2005-2009
Howard Hughes Medical Institute
2009
IFOM
2004
Max Planck Society
2004
Ubiquitin-conjugating enzymes (E2s) are key for protein turnover and quality control via ubiquitination. Some E2s also physically interact with the proteasome, but it remains undetermined which maintain proteostasis during aging. Here, we find that have diverse roles in handling a model aggregation-prone (huntingtin-polyQ) Drosophila retina: while some mediate aggregate assembly, UBE2D/effete (eff) other required huntingtin-polyQ degradation. UBE2D/eff is skeletal muscle: eff levels decline...
Drosophila larval skeletal muscles are single, multinucleated cells of different sizes that undergo tremendous growth within a few days. The mechanisms underlying this in concert with overall body unknown. We find the size individual correlates number nuclei per muscle cell and increasing nuclear ploidy during development. Inhibition Insulin receptor (InR; Insulin-like receptor)signaling autonomously reduces systemically affects other tissues, organs indeed entire body, most likely by...
Recent evidence indicates that skeletal muscle influences systemic aging, but little is known about the signaling pathways and muscle-released cytokines (myokines) responsible for this intertissue communication. Here, we show muscle-specific overexpression of transcription factor Mnt decreases age-related climbing defects extends lifespan in Drosophila. autonomously expression nucleolar components systemically rRNA levels size nucleolus adipocytes. This nonautonomous control nucleolus, a...
Aging is a risk factor for many human pathologies and characterized by extensive metabolic changes. Using targeted high-throughput metabolite profiling in Drosophila melanogaster at different ages, we demonstrate that methionine metabolism changes strikingly during aging. Methionine generates the methyl donor S-adenosyl-methionine (SAM), which converted via methylation to S-adenosyl-homocysteine (SAH), accumulates A RNAi screen against pathway components revealed significant life span...
Abstract Skeletal muscle regeneration involves coordinated interactions between different cell types. Injection of platelet-rich plasma is circumstantially considered an aid to repair but whether platelets promote beyond their role in hemostasis remains unexplored. Here, we find that signaling via platelet-released chemokines early event necessary for mice. Platelet depletion reduces the levels platelet-secreted neutrophil chemoattractants CXCL5 and CXCL7/PPBP. Consequently, early-phase...
Abstract Ubiquitination is a post-translational modification initiated by the E1 enzyme UBA1, which transfers ubiquitin to ~35 E2 ubiquitin-conjugating enzymes. While UBA1 loss cell lethal, it remains unknown how partial reduction in activity endured. Here, we utilize deep-coverage mass spectrometry define E1-E2 interactome and determine proteins that are modulated knockdown of each human cells. These analyses UBA1/E2-sensitive proteome specificity protein modulation. Interestingly, profound...
Skeletal muscle cell (myofiber) atrophy is a detrimental component of aging and cancer that primarily results from protein degradation via the proteasome ubiquitin ligases. Transcriptional upregulation some ligases contributes to myofiber atrophy, but little known about role most other play in this process. To address question, we have used RNAi screening Drosophila identify function > 320 evolutionarily conserved size regulation vivo. We find whereas for induces loss others (including N-end...
Abstract Sarcopenia is a degenerative condition that consists in age-induced atrophy and functional decline of skeletal muscle cells (myofibers). A common hypothesis inducing myofiber hypertrophy should also reinstate contractile function but such model has not been extensively tested. Here, we find the levels ubiquitin ligase UBR4 increase with aging, increases proteolytic activity proteasome. Importantly, muscle-specific loss rescues age-associated mice. However, reduces specific force...
Skeletal muscle atrophy is a debilitating condition that occurs with aging and disease, but the underlying mechanisms are incompletely understood. Previous work determined common transcriptional changes occur in during induced by different stimuli. However, whether this holds true at proteome level remains largely unexplored. Here, we find that, contrary to earlier model, distinct atrophic stimuli (corticosteroids, cancer cachexia, aging) induce mRNA protein mice. Moreover, there widespread...
Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging disease. Growth factors cytokines secreted by muscle, known as myokines, are important signaling factors, but it is largely unknown whether they growth differentiation response to nutrients. Here, we found that glucose increase the activity glucose-responsive transcription factor MLX (Max-like protein X), which promotes necessary for myoblast fusion. myogenesis not via an adjustment...
Abstract Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy the diaphragm, major responsible for breathing, an important determinant cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators myofiber growth. Subsequent testing mouse myotubes revealed Fibcd1...
Protein quality control is important for healthy aging and dysregulated in age-related diseases. The autophagy-lysosome ubiquitin-proteasome are key proteostasis, but it remains largely unknown whether other proteolytic systems also contribute to maintain proteostasis during aging. Here, we find that expression of enzymes (proteases/peptidases) distinct from the declines skeletal muscle Drosophila. Age-dependent protease downregulation undermines as demonstrated by increase...
Defects in protein quality control are the underlying cause of age-related diseases. The western blot analysis detergent-soluble and insoluble fractions has proven useful identifying interventions that regulate proteostasis. Here, we describe protocol for such analyses Drosophila tissues, mouse skeletal muscle, human organoids, HEK293 cells. We key adaptations this provide information will help modify future studies other tissues disease models. For complete details on use execution...