Publications by authors named "Fabio Demontis"

28 Publications

  • Page 1 of 1

Systemic manifestation and contribution of peripheral tissues to Huntington's disease pathogenesis.

Ageing Res Rev 2021 Aug 9;69:101358. Epub 2021 May 9.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Electronic address:

Huntington disease (HD) is an autosomal dominant neurodegenerative disease that is caused by expansion of cytosine/adenosine/guanine repeats in the huntingtin (HTT) gene, which leads to a toxic, aggregation-prone, mutant HTT-polyQ protein. Beyond the well-established mechanisms of HD progression in the central nervous system, growing evidence indicates that also peripheral tissues are affected in HD and that systemic signaling originating from peripheral tissues can influence the progression of HD in the brain. Herein, we review the systemic manifestation of HD in peripheral tissues, and the impact of systemic signaling on HD pathogenesis. Mutant HTT induces a body wasting syndrome (cachexia) primarily via its activity in skeletal muscle, bone, adipose tissue, and heart. Additional whole-organism effects induced by mutant HTT include decline in systemic metabolic homeostasis, which stems from derangement of pancreas, liver, gut, hypothalamic-pituitary-adrenal axis, and circadian functions. In addition to spreading via the bloodstream and a leaky blood brain barrier, HTT-polyQ may travel long distance via its uptake by neurons and its axonal transport from the peripheral to the central nervous system. Lastly, signaling factors that are produced and/or secreted in response to therapeutic interventions such as exercise or in response to mutant HTT activity in peripheral tissues may impact HD. In summary, these studies indicate that HD is a systemic disease that is influenced by intertissue signaling and by the action of pathogenic HTT in peripheral tissues. We propose that treatment strategies for HD should include the amelioration of HD symptoms in peripheral tissues. Moreover, harnessing signaling between peripheral tissues and the brain may provide a means for reducing HD progression in the central nervous system.
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http://dx.doi.org/10.1016/j.arr.2021.101358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205985PMC
August 2021

An age-downregulated ribosomal RpS28 protein variant regulates the muscle proteome.

G3 (Bethesda) 2021 May 11. Epub 2021 May 11.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Recent evidence indicates that the composition of the ribosome is heterogeneous and that multiple types of specialized ribosomes regulate the synthesis of specific protein subsets. In Drosophila, we find that expression of the ribosomal RpS28 protein variants RpS28a and RpS28-like preferentially occurs in the germline, a tissue resistant to aging, and that it significantly declines in skeletal muscle during aging. Muscle-specific overexpression of RpS28a at levels similar to those seen in the germline decreases early mortality and promotes the synthesis of a subset of proteins with known anti-aging roles, some of which have preferential expression in the germline. These findings indicate a contribution of specialized ribosomal proteins to the regulation of the muscle proteome during aging.
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http://dx.doi.org/10.1093/g3journal/jkab165DOI Listing
May 2021

Proteasome stress in skeletal muscle mounts a long-range protective response that delays retinal and brain aging.

Cell Metab 2021 Jun 26;33(6):1137-1154.e9. Epub 2021 Mar 26.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Neurodegeneration in the central nervous system (CNS) is a defining feature of organismal aging that is influenced by peripheral tissues. Clinical observations indicate that skeletal muscle influences CNS aging, but the underlying muscle-to-brain signaling remains unexplored. In Drosophila, we find that moderate perturbation of the proteasome in skeletal muscle induces compensatory preservation of CNS proteostasis during aging. Such long-range stress signaling depends on muscle-secreted Amyrel amylase. Mimicking stress-induced Amyrel upregulation in muscle reduces age-related accumulation of poly-ubiquitinated proteins in the brain and retina via chaperones. Preservation of proteostasis stems from the disaccharide maltose, which is produced via Amyrel amylase activity. Correspondingly, RNAi for SLC45 maltose transporters reduces expression of Amyrel-induced chaperones and worsens brain proteostasis during aging. Moreover, maltose preserves proteostasis and neuronal activity in human brain organoids challenged by thermal stress. Thus, proteasome stress in skeletal muscle hinders retinal and brain aging by mounting an adaptive response via amylase/maltose.
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http://dx.doi.org/10.1016/j.cmet.2021.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172468PMC
June 2021

Antagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging.

Nat Commun 2021 03 3;12(1):1418. Epub 2021 Mar 3.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Sarcopenia is a degenerative condition that consists in age-induced atrophy and functional decline of skeletal muscle cells (myofibers). A common hypothesis is that inducing myofiber hypertrophy should also reinstate myofiber contractile function but such model has not been extensively tested. Here, we find that the levels of the ubiquitin ligase UBR4 increase in skeletal muscle with aging, and that UBR4 increases the proteolytic activity of the proteasome. Importantly, muscle-specific UBR4 loss rescues age-associated myofiber atrophy in mice. However, UBR4 loss reduces the muscle specific force and accelerates the decline in muscle protein quality that occurs with aging in mice. Similarly, hypertrophic signaling induced via muscle-specific loss of UBR4/poe and of ESCRT members (HGS/Hrs, STAM, USP8) that degrade ubiquitinated membrane proteins compromises muscle function and shortens lifespan in Drosophila by reducing protein quality control. Altogether, these findings indicate that these ubiquitin ligases antithetically regulate myofiber size and muscle protein quality control.
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http://dx.doi.org/10.1038/s41467-021-21738-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930053PMC
March 2021

Muscle-derived Dpp regulates feeding initiation via endocrine modulation of brain dopamine biosynthesis.

Genes Dev 2020 01 12;34(1-2):37-52. Epub 2019 Dec 12.

Division of Developmental Biology, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

In animals, the brain regulates feeding behavior in response to local energy demands of peripheral tissues, which secrete orexigenic and anorexigenic hormones. Although skeletal muscle is a key peripheral tissue, it remains unknown whether muscle-secreted hormones regulate feeding. In , we found that (), the homolog of human bone morphogenetic proteins BMP2 and BMP4, is a muscle-secreted factor (a myokine) that is induced by nutrient sensing and that circulates and signals to the brain. Muscle-restricted dpp RNAi promotes foraging and feeding initiation, whereas overexpression reduces it. This regulation of feeding by muscle-derived Dpp stems from modulation of brain () expression and dopamine biosynthesis. Consistently, Dpp receptor signaling in dopaminergic neurons regulates expression and feeding initiation via the downstream transcriptional repressor Schnurri. Moreover, pharmacologic modulation of TH activity rescues the changes in feeding initiation due to modulation of expression in muscle. These findings indicate that muscle-to-brain endocrine signaling mediated by the myokine Dpp regulates feeding behavior.
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http://dx.doi.org/10.1101/gad.329110.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938663PMC
January 2020

A Key Role for the Ubiquitin Ligase UBR4 in Myofiber Hypertrophy in Drosophila and Mice.

Cell Rep 2019 07;28(5):1268-1281.e6

Division of Developmental Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address:

Skeletal muscle cell (myofiber) atrophy is a detrimental component of aging and cancer that primarily results from muscle protein degradation via the proteasome and ubiquitin ligases. Transcriptional upregulation of some ubiquitin ligases contributes to myofiber atrophy, but little is known about the role that most other ubiquitin ligases play in this process. To address this question, we have used RNAi screening in Drosophila to identify the function of > 320 evolutionarily conserved ubiquitin ligases in myofiber size regulation in vivo. We find that whereas RNAi for some ubiquitin ligases induces myofiber atrophy, loss of others (including the N-end rule ubiquitin ligase UBR4) promotes hypertrophy. In Drosophila and mouse myofibers, loss of UBR4 induces hypertrophy via decreased ubiquitination and degradation of a core set of target proteins, including the HAT1/RBBP4/RBBP7 histone-binding complex. Together, this study defines the repertoire of ubiquitin ligases that regulate myofiber size and the role of UBR4 in myofiber hypertrophy.
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http://dx.doi.org/10.1016/j.celrep.2019.06.094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697171PMC
July 2019

Circadian gene variants and the skeletal muscle circadian clock contribute to the evolutionary divergence in longevity across populations.

Genome Res 2019 08 27;29(8):1262-1276. Epub 2019 Jun 27.

Division of Developmental Biology, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Organisms use endogenous clocks to adapt to the rhythmicity of the environment and to synchronize social activities. Although the circadian cycle is implicated in aging, it is unknown whether natural variation in its function contributes to differences in lifespan between populations and whether the circadian clock of specific tissues is key for longevity. We have sequenced the genomes of strains with exceptional longevity that were obtained via multiple rounds of selection from a parental strain. Comparison of genomic, transcriptomic, and proteomic data revealed that changes in gene expression due to intergenic polymorphisms are associated with longevity and preservation of skeletal muscle function with aging in these strains. Analysis of transcription factors differentially modulated in long-lived versus parental strains indicates a possible role of circadian clock core components. Specifically, there is higher and and lower expression in the muscle of strains with delayed aging compared to the parental strain. These changes in the levels of circadian clock transcription factors lead to changes in the muscle circadian transcriptome, which includes genes involved in metabolism, proteolysis, and xenobiotic detoxification. Moreover, a skeletal muscle-specific increase in expression extends lifespan and recapitulates some of the transcriptional and circadian changes that differentiate the long-lived from the parental strains. Altogether, these findings indicate that the muscle circadian clock is important for longevity and that circadian gene variants contribute to the evolutionary divergence in longevity across populations.
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http://dx.doi.org/10.1101/gr.246884.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673717PMC
August 2019

Tissue-specific alteration of gene expression and function by RU486 and the GeneSwitch system.

NPJ Aging Mech Dis 2019 21;5. Epub 2019 May 21.

1Division of Developmental Biology, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105 USA.

The GeneSwitch (GS) is a modified Gal4/UAS system, whereby transgene expression is induced in by adding the drug RU486 to food. The GS system is routinely used in aging and behavioral studies to avoid confounding effects related to genetic background mutations. Here, we report transcriptional and functional defects that are induced by RU486 in a stock- and tissue-dependent manner, such as defects in flight and mitochondrial gene expression. In addition to including proper controls, our findings suggest that context-specific side effects induced by RU486 should be considered in the experimental design and when interpreting the observed phenotypes.
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http://dx.doi.org/10.1038/s41514-019-0036-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529481PMC
May 2019

Skeletal muscle autophagy and its role in sarcopenia and organismal aging.

Curr Opin Pharmacol 2017 06 10;34:1-6. Epub 2017 Apr 10.

Department of Developmental Neurobiology, Division of Developmental Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Sarcopenia, the loss of skeletal muscle mass and strength in the aged, is an important medical condition but its etiology is incompletely understood. Because autophagy promotes myofiber atrophy in the young, it was believed that autophagy inhibition would prevent sarcopenia. However, recent studies have revealed that autophagy actually maintains muscle mass and that its function declines during muscle aging. Consistently, boosting basal autophagy protects from age-related muscle dysfunction by promoting the selective degradation of misfolded proteins and dysfunctional organelles. Conversely, autophagy inhibition leads to loss of muscle strength and induces a maladaptive stress response responsible for myofiber atrophy in the aged. In addition to cell-autonomous effects, muscle autophagy and associated signaling pathways induce systemic responses in other aging tissues by modulating the expression and secretion of myokines. We propose that myokines and pharmacologic interventions that boost selective autophagy may prevent sarcopenia, delay systemic aging, and extend health span.
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http://dx.doi.org/10.1016/j.coph.2017.03.009DOI Listing
June 2017

Tissue-specific down-regulation of S-adenosyl-homocysteine via suppression of dAhcyL1/dAhcyL2 extends health span and life span in Drosophila.

Genes Dev 2016 06 16;30(12):1409-22. Epub 2016 Jun 16.

Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;

Aging is a risk factor for many human pathologies and is 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 is converted via methylation to S-adenosyl-homocysteine (SAH), which accumulates during aging. A targeted RNAi screen against methionine pathway components revealed significant life span extension in response to down-regulation of two noncanonical Drosophila homologs of the SAH hydrolase Ahcy (S-adenosyl-L-homocysteine hydrolase [SAHH[), CG9977/dAhcyL1 and Ahcy89E/CG8956/dAhcyL2, which act as dominant-negative regulators of canonical AHCY. Importantly, tissue-specific down-regulation of dAhcyL1/L2 in the brain and intestine extends health and life span. Furthermore, metabolomic analysis of dAhcyL1-deficient flies revealed its effect on age-dependent metabolic reprogramming and H3K4 methylation. Altogether, reprogramming of methionine metabolism in young flies and suppression of age-dependent SAH accumulation lead to increased life span. These studies highlight the role of noncanonical Ahcy enzymes as determinants of healthy aging and longevity.
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http://dx.doi.org/10.1101/gad.282277.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926864PMC
June 2016

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling.

Genes Dev 2015 Dec 19;29(23):2475-89. Epub 2015 Nov 19.

Department of Developmental Neurobiology, Division of Developmental Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors, but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we found that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX (Max-like protein X), which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin-like growth factor 2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned medium from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX-null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is manifested in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling.
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http://dx.doi.org/10.1101/gad.267419.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691951PMC
December 2015

Systemic Nutrient and Stress Signaling via Myokines and Myometabolites.

Annu Rev Physiol 2016 2;78:85-107. Epub 2015 Nov 2.

Division of Developmental Biology, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; email:

Homeostatic systems mount adaptive responses to meet the energy demands of the cell and to compensate for dysfunction in cellular compartments. Such surveillance systems are also active at the organismal level: Nutrient and stress sensing in one tissue can lead to changes in other tissues. Here, we review the emerging understanding of the role of skeletal muscle in regulating physiological homeostasis and disease progression in other tissues. Muscle-specific genetic interventions can induce systemic effects indirectly, via changes in the mass and metabolic demand of muscle, and directly, via the release of muscle-derived cytokines (myokines) and metabolites (myometabolites) in response to nutrients and stress. In turn, myokines and myometabolites signal to various target tissues in an autocrine, paracrine, and endocrine manner, thereby determining organismal resilience to aging, disease, and environmental challenges. We propose that tailoring muscle systemic signaling by modulating myokine and myometabolite levels may combat many degenerative diseases and delay aging.
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http://dx.doi.org/10.1146/annurev-physiol-021115-105305DOI Listing
December 2016

GDF11/myostatin and aging.

Aging (Albany NY) 2014 May;6(5):351-2

Medical School, Albert Einstein College of Medicine Bronx, NY 10461, USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069261PMC
http://dx.doi.org/10.18632/aging.100666DOI Listing
May 2014

Intertissue control of the nucleolus via a myokine-dependent longevity pathway.

Cell Rep 2014 Jun 29;7(5):1481-1494. Epub 2014 May 29.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.

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 that muscle-specific overexpression of the transcription factor Mnt decreases age-related climbing defects and extends lifespan in Drosophila. Mnt overexpression in muscle autonomously decreases the expression of nucleolar components and systemically decreases rRNA levels and the size of the nucleolus in adipocytes. This nonautonomous control of the nucleolus, a regulator of ribosome biogenesis and lifespan, relies on Myoglianin, a myokine induced by Mnt and orthologous to human GDF11 and Myostatin. Myoglianin overexpression in muscle extends lifespan and decreases nucleolar size in adipocytes by activating p38 mitogen-activated protein kinase (MAPK), whereas Myoglianin RNAi in muscle has converse effects. Altogether, these findings highlight a key role for myokine signaling in the integration of signaling events in muscle and distant tissues during aging.
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http://dx.doi.org/10.1016/j.celrep.2014.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125979PMC
June 2014

Whole-mount immunostaining of Drosophila skeletal muscle.

Nat Protoc 2013 Dec 14;8(12):2496-501. Epub 2013 Nov 14.

Department of Developmental Neurobiology, Division of Developmental Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Skeletal muscle undergoes marked functional decay during aging in humans, but the cell biological mechanisms responsible for this process are only partly known. Age-related muscle dysfunction is also a feature of aging in the fruit fly Drosophila melanogaster. Here we describe a detailed step-by-step protocol, which takes place over 3 d, for whole-mount immunostaining of Drosophila flight muscle. The skeletal muscle is fixed and permeabilized without any tissue freezing and dehydration so that antigens are accessible for staining with appropriate antibodies and the overall tissue ultrastructure is well preserved. This technique can be used to identify age-related cellular changes driving skeletal muscle aging and for characterizing models of human muscle disease in Drosophila.
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http://dx.doi.org/10.1038/nprot.2013.156DOI Listing
December 2013

Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models.

Dis Model Mech 2013 Nov 2;6(6):1339-52. Epub 2013 Oct 2.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

A characteristic feature of aged humans and other mammals is the debilitating, progressive loss of skeletal muscle function and mass that is known as sarcopenia. Age-related muscle dysfunction occurs to an even greater extent during the relatively short lifespan of the fruit fly Drosophila melanogaster. Studies in model organisms indicate that sarcopenia is driven by a combination of muscle tissue extrinsic and intrinsic factors, and that it fundamentally differs from the rapid atrophy of muscles observed following disuse and fasting. Extrinsic changes in innervation, stem cell function and endocrine regulation of muscle homeostasis contribute to muscle aging. In addition, organelle dysfunction and compromised protein homeostasis are among the primary intrinsic causes. Some of these age-related changes can in turn contribute to the induction of compensatory stress responses that have a protective role during muscle aging. In this Review, we outline how studies in Drosophila and mammalian model organisms can each provide distinct advantages to facilitate the understanding of this complex multifactorial condition and how they can be used to identify suitable therapies.
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http://dx.doi.org/10.1242/dmm.012559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820258PMC
November 2013

Mechanisms of muscle growth and atrophy in mammals and Drosophila.

Dev Dyn 2014 Feb 24;243(2):201-15. Epub 2013 Oct 24.

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts; Department of Oncology, IRCCS, Mario Negri Institute for Pharmacological Research, Milano, Italy.

Background: The loss of skeletal muscle mass (atrophy) that accompanies disuse and systemic diseases is highly debilitating. Although the pathogenesis of this condition has been primarily studied in mammals, Drosophila is emerging as an attractive system to investigate some of the mechanisms involved in muscle growth and atrophy.

Results: In this review, we highlight the outstanding unsolved questions that may benefit from a combination of studies in both flies and mammals. In particular, we discuss how different environmental stimuli and signaling pathways influence muscle mass and strength and how a variety of disease states can cause muscle wasting.

Conclusions: Studies in Drosophila and mammals should help identify molecular targets for the treatment of muscle wasting in humans.
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http://dx.doi.org/10.1002/dvdy.24036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980484PMC
February 2014

The influence of skeletal muscle on systemic aging and lifespan.

Aging Cell 2013 Dec 17;12(6):943-9. Epub 2013 Jul 17.

Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA; Division of Developmental Biology, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Epidemiological studies in humans suggest that skeletal muscle aging is a risk factor for the development of several age-related diseases such as metabolic syndrome, cancer, Alzheimer's and Parkinson's disease. Here, we review recent studies in mammals and Drosophila highlighting how nutrient- and stress-sensing in skeletal muscle can influence lifespan and overall aging of the organism. In addition to exercise and indirect effects of muscle metabolism, growing evidence suggests that muscle-derived growth factors and cytokines, known as myokines, modulate systemic physiology. Myokines may influence the progression of age-related diseases and contribute to the intertissue communication that underlies systemic aging.
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http://dx.doi.org/10.1111/acel.12126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3838468PMC
December 2013

Intramyocellular fatty-acid metabolism plays a critical role in mediating responses to dietary restriction in Drosophila melanogaster.

Cell Metab 2012 Jul;16(1):97-103

Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.

Changes in fat content have been associated with dietary restriction (DR), but whether they play a causal role in mediating various responses to DR remains unknown. We demonstrate that upon DR, Drosophila melanogaster shift their metabolism toward increasing fatty-acid synthesis and breakdown, which is required for various responses to DR. Inhibition of fatty-acid synthesis or oxidation genes specifically in the muscle tissue inhibited life-span extension upon DR. Furthermore, DR enhances spontaneous activity of flies, which was found to be dependent on the enhanced fatty-acid metabolism. This increase in activity was found to be at least partially required for the life-span extension upon DR. Overexpression of adipokinetic hormone (dAKH), the functional ortholog of glucagon, enhances fat metabolism, spontaneous activity, and life span. Together, these results suggest that enhanced fat metabolism in the muscle and physical activity play a key role in the protective effects of DR.
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http://dx.doi.org/10.1016/j.cmet.2012.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400463PMC
July 2012

FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging.

Cell 2010 Nov;143(5):813-25

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

The progressive loss of muscle strength during aging is a common degenerative event of unclear pathogenesis. Although muscle functional decline precedes age-related changes in other tissues, its contribution to systemic aging is unknown. Here, we show that muscle aging is characterized in Drosophila by the progressive accumulation of protein aggregates that associate with impaired muscle function. The transcription factor FOXO and its target 4E-BP remove damaged proteins at least in part via the autophagy/lysosome system, whereas foxo mutants have dysfunctional proteostasis. Both FOXO and 4E-BP delay muscle functional decay and extend life span. Moreover, FOXO/4E-BP signaling in muscles decreases feeding behavior and the release of insulin from producing cells, which in turn delays the age-related accumulation of protein aggregates in other tissues. These findings reveal an organism-wide regulation of proteostasis in response to muscle aging and a key role of FOXO/4E-BP signaling in the coordination of organismal and tissue aging.
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http://dx.doi.org/10.1016/j.cell.2010.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066043PMC
November 2010

Characterization of the Drosophila ortholog of the human Usher Syndrome type 1G protein sans.

PLoS One 2009 9;4(3):e4753. Epub 2009 Mar 9.

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Background: The Usher syndrome (USH) is the most frequent deaf-blindness hereditary disease in humans. Deafness is attributed to the disorganization of stereocilia in the inner ear. USH1, the most severe subtype, is associated with mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15, and sans. Myosin VIIa, harmonin, cadherin 23, and protocadherin 15 physically interact in vitro and localize to stereocilia tips in vivo, indicating that they form functional complexes. Sans, in contrast, localizes to vesicle-like structures beneath the apical membrane of stereocilia-displaying hair cells. How mutations in sans result in deafness and blindness is not well understood. Orthologs of myosin VIIa and protocadherin 15 have been identified in Drosophila melanogaster and their genetic analysis has identified essential roles in auditory perception and microvilli morphogenesis, respectively.

Principal Findings: Here, we have identified and characterized the Drosophila ortholog of human sans. Drosophila Sans is expressed in tubular organs of the embryo, in lens-secreting cone cells of the adult eye, and in microvilli-displaying follicle cells during oogenesis. Sans mutants are viable, fertile, and mutant follicle cells appear to form microvilli, indicating that Sans is dispensable for fly development and microvilli morphogenesis in the follicle epithelium. In follicle cells, Sans protein localizes, similar to its vertebrate ortholog, to intracellular punctate structures, which we have identified as early endosomes associated with the syntaxin Avalanche.

Conclusions: Our work is consistent with an evolutionary conserved function of Sans in vesicle trafficking. Furthermore it provides a significant basis for further understanding of the role of this Usher syndrome ortholog in development and disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004753PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649435PMC
May 2009

Integration of Insulin receptor/Foxo signaling and dMyc activity during muscle growth regulates body size in Drosophila.

Development 2009 Mar 11;136(6):983-93. Epub 2009 Feb 11.

Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

Drosophila larval skeletal muscles are single, multinucleated cells of different sizes that undergo tremendous growth within a few days. The mechanisms underlying this growth in concert with overall body growth are unknown. We find that the size of individual muscles correlates with the number of nuclei per muscle cell and with increasing nuclear ploidy during development. Inhibition of Insulin receptor (InR; Insulin-like receptor) signaling in muscles autonomously reduces muscle size and systemically affects the size of other tissues, organs and indeed the entire body, most likely by regulating feeding behavior. In muscles, InR/Tor signaling, Foxo and dMyc (Diminutive) are key regulators of endoreplication, which is necessary but not sufficient to induce growth. Mechanistically, InR/Foxo signaling controls cell cycle progression by modulating dmyc expression and dMyc transcriptional activity. Thus, maximal dMyc transcriptional activity depends on InR to control muscle mass, which in turn induces a systemic behavioral response to allocate body size and proportions.
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http://dx.doi.org/10.1242/dev.027466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727562PMC
March 2009

Apical and lateral cell protrusions interconnect epithelial cells in live Drosophila wing imaginal discs.

Dev Dyn 2007 Dec;236(12):3408-18

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Communication among cells by means of the exchange of signaling cues is important for tissue and organ development. Recent reports indicate that one way that signaling cues can be delivered is by movement along cellular protrusions interconnecting cells. Here, by using confocal laser scanning microscopy and three-dimensional rendering, we describe in Drosophila melanogaster wing imaginal discs lateral protrusions interconnecting cells of the columnar epithelium. Moreover, we identified protrusions of the apical surface of columnar cells that reached and apparently contacted cells of the overlying squamous epithelium. Both apical and lateral protrusions could be visualized by expression of Tkv-GFP, a green fluorescent protein (GFP) -tagged version of a receptor of the Dpp/BMP4 signaling molecule, and the endosome marker GFP-Rab5. Our results demonstrate a previously unexpected richness of cellular protrusions within wing imaginal discs and support the view that cellular protrusions may provide a means for exchanging signaling cues between cells.
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http://dx.doi.org/10.1002/dvdy.21324DOI Listing
December 2007

PDZ-domain-binding sites are common among cadherins.

Dev Genes Evol 2006 Nov 5;216(11):737-41. Epub 2006 Oct 5.

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307, Dresden, Germany.

Cadherins are Ca(2+)-dependent cell adhesion molecules that play fundamental roles in animal development and homeostasis. A number of cadherins contain conserved binding sites for catenins in their cytoplasmic region that are important for the adhesive function of these cadherins by mediating their interaction to the cytoskeleton. However, most cadherins lack apparent binding sites for catenins and their cytoplasmic interacting partners are mostly unknown. In this paper, we show, using bioinformatics, that a number of insect and vertebrate cadherins lacking catenin-binding sites contain conserved consensus sequences for C-terminal PSD-95/Discs-large/ZO-1 (PDZ)-domain-binding sites. This suggests that PDZ-domain-containing proteins are common cytoplasmic interacting partners for cadherins lacking catenin-binding sites.
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http://dx.doi.org/10.1007/s00427-006-0097-0DOI Listing
November 2006

Cadherin Cad99C is required for normal microvilli morphology in Drosophila follicle cells.

J Cell Sci 2006 Mar 28;119(Pt 6):1184-95. Epub 2006 Feb 28.

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.

Microvilli are actin-filled membranous extensions common to epithelial cells. Several proteins have been identified that localize to microvilli. However, most of these proteins are dispensable for the normal morphogenesis of microvilli. Here, we show by immunoelectron microscopy that the non-classical cadherin Cad99C localizes to microvilli of Drosophila ovarian follicle cells. Loss of Cad99C function leads to disorganized and abnormal follicle cell microvilli. Conversely, overexpression of Cad99C in follicle cells results in large bundles of microvilli. Furthermore, altered microvilli morphology correlates with defects in the assembly of the vitelline membrane, an extracellular layer secreted by follicle cells that is part of the eggshell. Finally, we provide evidence that Cad99C is the homolog of vertebrate protocadherin 15. Mutations in the gene encoding protocadherin 15 lead to the disorganization of stereocilia, which are microvilli-derived extensions of cochlear hair cells, and deafness (Usher syndrome type 1F). Our data suggest an essential role for Cad99C in microvilli morphogenesis that is important for follicle cell function. Furthermore, these results indicate that insects and vertebrates use related cadherins to organize microvilli-like cellular extensions.
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http://dx.doi.org/10.1242/jcs.02831DOI Listing
March 2006

Cadherin Cad99C is regulated by Hedgehog signaling in Drosophila.

Dev Biol 2005 Mar;279(1):142-54

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.

The subdivision of the Drosophila wing imaginal disc into anterior and posterior compartments requires a transcriptional response to Hedgehog signaling. However, the genes regulated by Hedgehog signal transduction that mediate the segregation of anterior and posterior cells have not been identified. Here, we molecularly characterize the previously predicted gene cad99C and show that it is regulated by Hedgehog signaling. Cad99C encodes a transmembrane protein with a molecular weight of approximately 184 kDa that contains 11 cadherin repeats in its extracellular domain and a conserved type I PDZ-binding site at its C-terminus. The levels of cad99C RNA and protein are low throughout the wing imaginal disc. However, in the pouch region, these levels are elevated in a strip of anterior cells along the A/P boundary where the Hedgehog signal is transduced. Ectopic expression of Hedgehog, or the Hedgehog-regulated transcription factor Cubitus interruptus, induces high-level expression of Cad99C. Conversely, blocking Hedgehog signal transduction by either inactivating Smoothened or Cubitus interruptus reduces high-level Cad99C expression. Finally, by analyzing mutant clones of cells, we show that Cad99C is not essential for cell segregation at the A/P boundary. We conclude that cad99C is a novel Hedgehog-regulated gene encoding a member of the cadherin superfamily in Drosophila.
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http://dx.doi.org/10.1016/j.ydbio.2004.12.008DOI Listing
March 2005

Nanotubes make big science.

Authors:
Fabio Demontis

PLoS Biol 2004 Jul 13;2(7):E215. Epub 2004 Jul 13.

International Max Planck Research School working with Christian Dahmann at the Max Planck Institute for Cell Biology and Genetics in Dresden, Germany.

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http://dx.doi.org/10.1371/journal.pbio.0020215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC449900PMC
July 2004

VE-cadherin expression and clustering maintain low levels of survivin in endothelial cells.

Am J Pathol 2004 Jul;165(1):181-9

Italian Foundation for Cancer Research, Institute of Molecular Oncology, Milan, Italy.

Survivin is strongly expressed in embryonic organs and in tumor cells but is low or absent in differentiated normal tissues. Resting endothelium expresses low levels of survivin but can up-regulate its synthesis on activation to proliferate. The mechanisms responsible for survivin down-regulation in resting conditions are still unknown. We report here that confluence and vascular endothelial-cadherin (VE-cadherin) expression induce contact inhibition of cell growth and survivin down-regulation in the endothelium. Using beta-catenin null and positive isogenic endothelial cell lines we found that the effect requires beta-catenin expression and its association to VE-cadherin cytoplasmic tail. Furthermore, in allantois organ cultures, survivin expression is up-regulated in areas of growing vessels where VE-cadherin is partially dismantled from junctions or in VE-cadherin -/- specimens. Overall, these data indicate that VE-cadherin and beta-catenin may negatively regulate survivin synthesis in endothelial cells. Consistently, in epidermal and pancreatic cell lines or ovarian tumors, epithelial-cadherin (E-cadherin) and survivin expression is inversely related, suggesting a non-cell-specific role of cadherins in reducing survivin synthesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618523PMC
http://dx.doi.org/10.1016/S0002-9440(10)63287-7DOI Listing
July 2004