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Rochester, MN, United States

LeBrasseur N.K.,Robert and Arlene Kogod Center on Aging | LeBrasseur N.K.,Mayo Medical School
Diabetologia | Year: 2012

The obesity epidemic is an overwhelming global health concern. Interventions to improve body weight and composition aim to restore balance between nutrient intake and energy expenditure. Myostatin, a powerful negative regulator of skeletal muscle mass, has emerged as a potential therapeutic target for obesity and type 2 diabetes mellitus because of the prominent role skeletal muscle plays in metabolic rate and insulin-mediated glucose disposal. In fact, inhibition of myostatin by genetic manipulation or pharmacological means leads to a hypermuscular and very lean build in mice. The resistance of myostatin-null mice to diet-induced obesity, fat mass accumulation and metabolic dysfunction has been presumed to be a result of their large skeletal muscle mass; however, in this issue of Diabetologia, Zhang et al. (doi:10.1007/s00125-011-2304-4) provide evidence that myostatin inhibition also significantly impacts the phenotype of white adipose tissue (WAT). The authors reveal elevated expression of key metabolic genes of fatty acid transport and oxidation and, intriguingly, the presence of brown adipose tissue-like cells in WAT of myostatin-null mice. They also show that pharmacological inhibition of myostatin replicates several of the protective benefits conveyed by its genetic inactivation. Herein, these data, areas in need of further investigation and the evidence that implicates myostatin as a target for obesity and type 2 diabetes mellitus are discussed. © 2011 Springer-Verlag. Source


Scrable H.,Robert and Arlene Kogod Center on Aging
Science Translational Medicine | Year: 2012

Research reported in this issue of Science Translational Medicine illustrates the benefits of short-term food withdrawal (fasting) in the treatment of cancer. Fasting exploited fundamental differences in the way tumor cells and normal cells respond to stress, simultaneously strengthening normal cell function and weakening tumor cell survival in the presence of toxic doses of chemotherapeutic drugs. Source


LeBrasseur N.K.,Robert and Arlene Kogod Center on Aging | Walsh K.,Boston University | Arany Z.,Beth Israel Deaconess Medical Center
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

Skeletal muscle exhibits remarkable plasticity with respect to its metabolic properties. Recent work has shown that interventions such as resistance training, genetic alterations and pharmacological strategies that increase muscle mass and glycolytic capacity, and not necessarily oxidative competence, can improve body composition and systemic metabolism. We review here recent advances in our understanding of the signaling and transcriptional regulatory pathways of this strategy and review new evidence obtained from mice and humans that supports the notion that increasing muscle mass and glycolytic capacity may effectively counter insulin resistance and type 2 diabetes mellitus. Copyright © 2011 the American Physiological Society. Source


Kirkland J.L.,Robert and Arlene Kogod Center on Aging
Cold Spring Harbor Perspectives in Medicine | Year: 2016

Life and health span have been extended in experimental animals using drugs that are potentially translatable into humans. Considerable effort is needed beyond the usual steps in drug development to devise the models, and realistic preclinical and clinical trial strategies are required to advance these agents into clinical application. It will be important to focus on subjects who already have symptoms or are at imminent risk of developing disorders related to fundamental aging processes, to use short-term, clinically relevant outcomes, as opposed to long-term outcomes, such as health span or life span, and to validate endpoint measures so they are acceptable to regulatory agencies. Funding is a roadblock, as is shortage of investigators with combined expertise in the basic biology of aging, clinical geriatrics, and investigational new drug clinical trials. Strategies for developing a path from the bench to the bedside are reviewed for interventions that target fundamental aging mechanisms. © 2016 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Oursler M.J.,Robert and Arlene Kogod Center on Aging
Journal of Cellular Biochemistry | Year: 2010

Bone marrow macrophages fuse on the bone surface to form multinucleated osteoclasts that then organize to efficiently resorb bone. Many, if not all, of the stages of macrophage fusion involve cytoskeletal components that reorganize the cells. Recruitment may involve chemotactic responses to bone matrix protein and calcium ion gradients and/or chemokine production by bone forming osteoblasts. The roles of integrins vary, depending on the particular subunits with some interfering with fusion and others having a participatory role. RANKL is essential for fusion and many identified modulators of fusion influence RANKL signaling pathways. Tetraspanins have been implicated in fusion of macrophages and myoblasts, but differences in impacts exist between these two cell types. Macrophage recruitment to apoptotic cells prior to their engulfment is driven by the exposed phospholipids on the external surface of the apoptotic cells and there is evidence that this same identification mechanism is employed in macrophage fusion. Because loss of cadherin or ADAM family members suppresses macrophage fusion, a crucial role for these membrane glycoproteins is evident. The Ig membrane glycoprotein superfamily members CD200 and MFR/ SIRPa are involved in macrophage fusion, although their influences are unresolved. Differential screenings have identified the structurally related membrane proteins DC-STAMP and OC-STAMP as required components for fusion and the contributions to fusion remain active areas of investigation. While many of the key components involved in these processes have been identified, a great deal of work remains in resolving the precise processes involved and the interactions between key contributors to multinucleated osteoclast formation. © 2010 Wiley-Liss, Inc. Source

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