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1.
Elife ; 112022 03 17.
Article in English | MEDLINE | ID: mdl-35297761

ABSTRACT

The loss of skeletal muscle function with age, known as sarcopenia, significantly reduces independence and quality of life and can have significant metabolic consequences. Although exercise is effective in treating sarcopenia it is not always a viable option clinically, and currently, there are no pharmacological therapeutic interventions for sarcopenia. Here, we show that chronic treatment with pan-adiponectin receptor agonist AdipoRon improved muscle function in male mice by a mechanism linked to skeletal muscle metabolism and tissue remodeling. In aged mice, 6 weeks of AdipoRon treatment improved skeletal muscle functional measures in vivo and ex vivo. Improvements were linked to changes in fiber type, including an enrichment of oxidative fibers, and an increase in mitochondrial activity. In young mice, 6 weeks of AdipoRon treatment improved contractile force and activated the energy-sensing kinase AMPK and the mitochondrial regulator PGC-1a (peroxisome proliferator-activated receptor gamma coactivator one alpha). In cultured cells, the AdipoRon induced stimulation of AMPK and PGC-1a was associated with increased mitochondrial membrane potential, reorganization of mitochondrial architecture, increased respiration, and increased ATP production. Furthermore, the ability of AdipoRon to stimulate AMPK and PGC1a was conserved in nonhuman primate cultured cells. These data show that AdipoRon is an effective agent for the prevention of sarcopenia in mice and indicate that its effects translate to primates, suggesting it may also be a suitable therapeutic for sarcopenia in clinical application.


Subject(s)
Adiponectin , Receptors, Adiponectin , Adiponectin/metabolism , Animals , Male , Mice , Muscle, Skeletal/metabolism , Piperidines , Primates , Quality of Life , Receptors, Adiponectin/metabolism
2.
Nat Commun ; 10(1): 3929, 2019 09 02.
Article in English | MEDLINE | ID: mdl-31477734

ABSTRACT

AT-1/SLC33A1 is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation. Dysfunctional ER acetylation, as caused by heterozygous or homozygous mutations as well as gene duplication events of AT-1/SLC33A1, has been linked to both developmental and degenerative diseases. Here, we investigate two models of AT-1 dysregulation and altered acetyl-CoA flux: AT-1S113R/+ mice, a model of AT-1 haploinsufficiency, and AT-1 sTg mice, a model of AT-1 overexpression. The animals display distinct metabolic adaptation across intracellular compartments, including reprogramming of lipid metabolism and mitochondria bioenergetics. Mechanistically, the perturbations to AT-1-dependent acetyl-CoA flux result in global and specific changes in both the proteome and the acetyl-proteome (protein acetylation). Collectively, our results suggest that AT-1 acts as an important metabolic regulator that maintains acetyl-CoA homeostasis by promoting functional crosstalk between different intracellular organelles.


Subject(s)
Acetyl Coenzyme A/metabolism , Cytosol/metabolism , Lipid Metabolism , Membrane Transport Proteins/metabolism , Proteome/metabolism , Proteomics/methods , Acetylation , Animals , Endoplasmic Reticulum/metabolism , Haploinsufficiency , Liver/cytology , Liver/metabolism , Lysine/metabolism , Membrane Transport Proteins/genetics , Mice, Knockout , Mice, Transgenic
3.
Aging Cell ; 18(5): e12999, 2019 10.
Article in English | MEDLINE | ID: mdl-31267675

ABSTRACT

Deleterious changes in energy metabolism have been linked to aging and disease vulnerability, while activation of mitochondrial pathways has been linked to delayed aging by caloric restriction (CR). The basis for these associations is poorly understood, and the scope of impact of mitochondrial activation on cellular function has yet to be defined. Here, we show that mitochondrial regulator PGC-1a is induced by CR in multiple tissues, and at the cellular level, CR-like activation of PGC-1a impacts a network that integrates mitochondrial status with metabolism and growth parameters. Transcriptional profiling reveals that diverse functions, including immune pathways, growth, structure, and macromolecule homeostasis, are responsive to PGC-1a. Mechanistically, these changes in gene expression were linked to chromatin remodeling and RNA processing. Metabolic changes implicated in the transcriptional data were confirmed functionally including shifts in NAD metabolism, lipid metabolism, and membrane lipid composition. Delayed cellular proliferation, altered cytoskeleton, and attenuated growth signaling through post-transcriptional and post-translational mechanisms were also identified as outcomes of PGC-1a-directed mitochondrial activation. Furthermore, in vivo in tissues from a genetically heterogeneous mouse population, endogenous PGC-1a expression was correlated with this same metabolism and growth network. These data show that small changes in metabolism have broad consequences that arguably would profoundly alter cell function. We suggest that this PGC-1a sensitive network may be the basis for the association between mitochondrial function and aging where small deficiencies precipitate loss of function across a spectrum of cellular activities.


Subject(s)
Caloric Restriction , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , 3T3-L1 Cells , Animals , Cells, Cultured , Cellular Senescence , Energy Metabolism , Mice , Mitochondria/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
4.
EBioMedicine ; 21: 37-44, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28648985

ABSTRACT

Aging as a research pursuit is fairly new compared with traditional lines of medical research. A growing field of investigators is focused on understanding how changes in tissue biology, physiology, and systemic homeostasis, conspire to create increased vulnerability to disease as a function of age. Aging research as a discipline is necessarily broad; in part because aging itself is multi-faceted and in part because different model systems are employed to define the underlying biology. In this review we outline aspects of aging research that are likely to uncover the pivotal events leading to age-related disease vulnerability. We focus on studies of human aging and discuss the value of research on caloric restriction, an intervention with proven efficacy in delaying aging. We propose that studies such as these will deliver target factors and processes that create vulnerability in human aging, an advance that would potentially be transformative in clinical care.


Subject(s)
Aging/physiology , Caloric Restriction , Animals , Energy Metabolism , Humans , Signal Transduction , Translational Research, Biomedical
5.
Aging Cell ; 16(3): 497-507, 2017 06.
Article in English | MEDLINE | ID: mdl-28156058

ABSTRACT

Adipose tissue expansion has been associated with system-wide metabolic dysfunction and increased vulnerability to diabetes, cancer, and cardiovascular disease. A reduction in adiposity is a hallmark of caloric restriction (CR), an intervention that extends longevity and delays the onset of these same age-related conditions. Despite these parallels, the role of adipose tissue in coordinating the metabolism of aging is poorly defined. Here, we show that adipose tissue metabolism and secretory profiles change with age and are responsive to CR. We conducted a cross-sectional study of CR in adult, late-middle-aged, and advanced-aged mice. Adiposity and the relationship between adiposity and circulating levels of the adipose-derived peptide hormone adiponectin were age-sensitive. CR impacted adiposity but only levels of the high molecular weight isoform of adiponectin responded to CR. Activators of metabolism including PGC-1a, SIRT1, and NAMPT were differentially expressed with CR in adipose tissues. Although age had a significant impact on NAD metabolism, as detected by biochemical assay and multiphoton imaging, the impact of CR was subtle and related to differences in reliance on oxidative metabolism. The impact of age on circulating lipids was limited to composition of circulating phospholipids. In contrast, the impact of CR was detected in all lipid classes regardless of age, suggesting a profound difference in lipid metabolism. These data demonstrate that aspects of adipose tissue metabolism are life phase specific and that CR is associated with a distinct metabolic state, suggesting that adipose tissue signaling presents a suitable target for interventions to delay aging.


Subject(s)
Adiponectin/genetics , Adipose Tissue/metabolism , Adiposity/genetics , Aging/metabolism , Caloric Restriction , Lipids/blood , Adiponectin/metabolism , Animals , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation, Developmental , Lipids/classification , Male , Mice , Nicotinamide Phosphoribosyltransferase/genetics , Nicotinamide Phosphoribosyltransferase/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Signal Transduction , Sirtuin 1/genetics , Sirtuin 1/metabolism
6.
Bioorg Med Chem ; 19(18): 5446-53, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21855351

ABSTRACT

Assembly of a bipolar mitotic spindle requires the action of class 5 kinesins, and inhibition or depletion of this motor results in mitotic arrest and apoptosis. S-Trityl-l-cysteine is an allosteric inhibitor of vertebrate Kinesin Spindle Protein (KSP) that has generated considerable interest due to its anti-cancer properties, however, poor pharmacological properties have limited the use of this compound. We have modified the triphenylmethyl and cysteine groups, guided by biochemical and cell-based assays, to yield new cysteinol and cysteamine derivatives with increased inhibitory activity, greater efficacy in model systems, and significantly enhanced potency against the NCI60 tumor panel. These results reveal a promising new class of conformationally-flexible small molecules as allosteric KSP inhibitors for use as research tools, with activities that provide impetus for further development as anti-tumor agents.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cysteamine/analogs & derivatives , Kinesins/antagonists & inhibitors , Trityl Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , Cysteamine/chemical synthesis , Cysteamine/chemistry , Cysteamine/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Embryo, Nonmammalian/drug effects , HeLa Cells , Humans , Models, Molecular , Molecular Structure , Sea Urchins/drug effects , Sea Urchins/embryology , Stereoisomerism , Structure-Activity Relationship , Trityl Compounds/chemical synthesis , Trityl Compounds/chemistry
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