Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila

Huntington’s disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we used Drosophila models to determine that Htt-PQ aggregation in the heart causes shortened lifespan and cardiac dysfunction that is ameliorated by promoting chaperonin function or reducing oxidative stress. Here, we further study the role of neuronal mutant huntingtin and how it affects peripheral function. We overexpressed normal (Htt-PQ25) or expanded mutant (Htt-PQ72) exon 1 of huntingtin in Drosophila neurons and found that mutant huntingtin caused age-dependent Htt-PQ aggregation in the brain and could cause a loss of synapsin. To determine if this neuronal dysfunction led to peripheral dysfunction, we performed a negative geotaxis assay to measure locomotor performance and found that neuronal mutant huntingtin caused an age-dependent decrease in locomotor performance. Next, we found that rapamycin reduced Htt-PQ aggregation in the brain. These results demonstrate the role of neuronal Htt-PQ in dysfunction in models of HD, suggest that brain-periphery crosstalk could be important to the pathogenesis of HD, and show that rapamycin reduces mutant huntingtin aggregation in the brain

When a calorie is not just a calorie : Diet quality and timing as mediators of metabolism and healthy aging

Funding Information: We thank Dr. Yih-Woei Fridell of the National Institute on Aging for organizing the meeting, as well as the NIA Division of Aging Biology for their support. We thank Dr. Gino Cortopassi for his edits and suggestions. The figures were created with BioRender.com. The Mihaylova lab is supported in part by the NIA (R00AG054760), Office of the NIH Director (DP2CA271361), the American Federation for Aging Research, the V Foundation, Pew Biomedical Scholar award, and startup funds from the Ohio State University. The Delibegovic lab is funded by the British Heart Foundation, Diabetes UK, BBSRC, NHS Grampian, Tenovus Scotland, and the Development Trust (University of Aberdeen). J.J.R. is supported by NIA PO1AG062817, R21AG064290, and R21AG071156. Research support for J.B. was from NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK127800, R01DK113011, R01DK090625, and R01DK050203 and the National Institute on Aging (NIA) grants R01AG065988 and P01AG011412, as well as the University of Chicago Diabetes Research and Training Center grant P30DK020595. This work was supported by NIH grants AG065992 to G.M. and AG068550 to G.M. and S.P. as well as UAB Startup funds 3123226 and 3123227 to G.M. R.S. is supported by NIH grants RF1AG043517, R01AG065985, R01DK123327, R56AG074568, and P01AG031782. Z.C. is primarily funded by The Welch Foundation (AU-1731-20190330) and NIH/NIA (R01AG065984, R56AG063746, RF1AG061901, and R56AG076144). A.C. is supported by NIA grant R01AG065993. W.W.J. is supported by the NIH (R01DC020031). M.S.-H. is supported by NIH R01 R35GM127049, R01 AG045842, and R21 NS122366. The research in the Dixit lab was supported in part by NIH grants AG031797, AG045712, P01AG051459, AR070811, AG076782, AG073969, and AG068863 and Cure Alzheimer's Fund (CAF). A.E.T.-M. is supported by the NIH/NIA (AG075059 and AG058630), NIAMS (AR071133), NHLBI (HL153460), pilot and feasibility funds from the NIDDK-funded UAB Nutrition Obesity Research Center (DK056336) and the NIA-funded UAB Nathan Shock Center (AG050886), and startup funds from UAB. J.A.M. is supported by the Intramural Research Program, NIA, NIH. The Panda lab is supported by the NIH (R01CA236352, R01CA258221, RF1AG068550, and P30CA014195), the Wu Tsai Human Performance Alliance, and the Joe and Clara Tsai Foundation. The Lamming lab is supported in part by the NIA (AG056771, AG062328, AG061635, and AG081482), the NIDDK (DK125859), startup funds from UW-Madison, and the U.S. Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government. D.W.L. has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. S.P. is the author of the books The Circadian Code and The Circadian Diabetes Code. Funding Information: We thank Dr. Yih-Woei Fridell of the National Institute on Aging for organizing the meeting, as well as the NIA Division of Aging Biology for their support. We thank Dr. Gino Cortopassi for his edits and suggestions. The figures were created with BioRender.com . The Mihaylova lab is supported in part by the NIA ( R00AG054760 ), Office of the NIH Director ( DP2CA271361 ), the American Federation for Aging Research , the V Foundation , Pew Biomedical Scholar award, and startup funds from the Ohio State University . The Delibegovic lab is funded by the British Heart Foundation , Diabetes UK , BBSRC , NHS Grampian , Tenovus Scotland , and the Development Trust ( University of Aberdeen ). J.J.R. is supported by NIA PO1AG062817 , R21AG064290 , and R21AG071156 . Research support for J.B. was from NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK127800 , R01DK113011 , R01DK090625 , and R01DK050203 and the National Institute on Aging (NIA) grants R01AG065988 and P01AG011412 , as well as the University of Chicago Diabetes Research and Training Center grant P30DK020595 . This work was supported by NIH grants AG065992 to G.M. and AG068550 to G.M. and S.P., as well as UAB Startup funds 3123226 and 3123227 to G.M. R.S. is supported by NIH grants RF1AG043517 , R01AG065985 , R01DK123327 , R56AG074568 , and P01AG031782 . Z.C. is primarily funded by The Welch Foundation ( AU-1731-20190330 ) and NIH/NIA ( R01AG065984 , R56AG063746 , RF1AG061901 , and R56AG076144 ). A.C. is supported by NIA grant R01AG065993 . W.W.J. is supported by the NIH ( R01DC020031 ). M.S.-H. is supported by NIH R01 R35GM127049 , R01 AG045842 , and R21 NS122366 . The research in the Dixit lab was supported in part by NIH grants AG031797 , AG045712 , P01AG051459 , AR070811 , AG076782 , AG073969 , and AG068863 and Cure Alzheimer's Fund (CAF). A.E.T.-M. is supported by the NIH/NIA ( AG075059 and AG058630 ), NIAMS ( AR071133 ), NHLBI ( HL153460 ), pilot and feasibility funds from the NIDDK -funded UAB Nutrition Obesity Research Center ( DK056336 ) and the NIA -funded UAB Nathan Shock Center ( AG050886 ), and startup funds from UAB . J.A.M. is supported by the Intramural Research Program, NIA, NIH . The Panda lab is supported by the NIH ( R01CA236352 , R01CA258221 , RF1AG068550 , and P30CA014195 ), the Wu Tsai Human Performance Alliance , and the Joe and Clara Tsai Foundation . The Lamming lab is supported in part by the NIA ( AG056771 , AG062328 , AG061635 , and AG081482 ), the NIDDK ( DK125859 ), startup funds from UW-Madison , and the U.S. Department of Veterans Affairs ( I01-BX004031 ), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government.Peer reviewedPostprin

The UNC-45 Chaperone Is Critical for Establishing Myosin-Based Myofibrillar Organization and Cardiac Contractility in the Drosophila Heart Model

UNC-45 is a UCS (UNC-45/CRO1/She4P) class chaperone necessary for myosin folding and/or accumulation, but its requirement for maintaining cardiac contractility has not been explored. Given the prevalence of myosin mutations in eliciting cardiomyopathy, chaperones like UNC-45 are likely to be equally critical in provoking or modulating myosin-associated cardiomyopathy. Here, we used the Drosophila heart model to examine its role in cardiac physiology, in conjunction with RNAi-mediated gene silencing specifically in the heart in vivo. Analysis of cardiac physiology was carried out using high-speed video recording in conjunction with movement analysis algorithms. unc-45 knockdown resulted in severely compromised cardiac function in adults as evidenced by prolonged diastolic and systolic intervals, and increased incidence of arrhythmias and extreme dilation; the latter was accompanied by a significant reduction in muscle contractility. Structural analysis showed reduced myofibrils, myofibrillar disarray, and greatly decreased cardiac myosin accumulation. Cardiac unc-45 silencing also dramatically reduced life-span. In contrast, third instar larval and young pupal hearts showed mild cardiac abnormalities, as severe cardiac defects only developed during metamorphosis. Furthermore, cardiac unc-45 silencing in the adult heart (after metamorphosis) led to less severe phenotypes. This suggests that UNC-45 is mostly required for myosin accumulation/folding during remodeling of the forming adult heart. The cardiac defects, myosin deficit and decreased life-span in flies upon heart-specific unc-45 knockdown were significantly rescued by UNC-45 over-expression. Our results are the first to demonstrate a cardiac-specific requirement of a chaperone in Drosophila, suggestive of a critical role of UNC-45 in cardiomyopathies, including those associated with unfolded proteins in the failing human heart. The dilated cardiomyopathy phenotype associated with UNC-45 deficiency is mimicked by myosin knockdown suggesting that UNC-45 plays a crucial role in stabilizing myosin and possibly preventing human cardiomyopathies associated with functional deficiencies of myosin

A Skeletal Muscle-Centric View on Time-Restricted Feeding and Obesity under Various Metabolic Challenges in Humans and Animals

Nearly 50% of adults will suffer from obesity in the U.S. by 2030. High obesity rates can lead to high economic and healthcare burdens in addition to elevated mortality rates and reduced health span in patients. Emerging data demonstrate that obesity is a multifactorial complex disease with various etiologies including aging, a lifestyle of chronic high-fat diets (HFD), genetic predispositions, and circadian disruption. Time-restricted feeding/eating (TRF; TRE in humans) is an intervention demonstrated by studies to show promise as an effective alternative therapy for ameliorating the effects of obesity and metabolic disease. New studies have recently suggested that TRF/TRE modulates the skeletal muscle which plays a crucial role in metabolism historically observed to be impaired under obesity. Here we discuss recent findings regarding potential mechanisms underlying TRF’s modulation of skeletal muscle function, metabolism, and structure which may shed light on future research related to TRF as a solution to obesity