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Plenary Speakers

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David A. Hood
Date
June 16, 2016 11:30
Speaker
David A. Hood   CV
Affiliation
York University, Canada
Title
Mitochondrial turnover in muscle during exercise and chronic disuse
Abstract

Muscle is a metabolic tissue that possesses a remarkable capacity for phenotypic adaptations. Mitochondria are central for enhanced muscle metabolism, and adaptations to exercise include increases in organelle content and its reticular network. Mitochondrial content is dependent on the balance between biogenesis and degradation, termed mitochondrial turnover. Biogenesis is known to occur with exercise, and is largely regulated through the coordinate expression of numerous nuclear and mitochondrial genes governed by transcription factors such as p53, as well as the transcriptional co-activator PGC-1α. The activation of transcription as a result of exercise may initially be mediated by signals originating from within mitochondria, possibly driven by an unfolded protein response (UPR). In contrast, the regulation of mitochondrial degradation (i.e. mitophagy) by exercise is less well understood. Our research has indicated that mitochondrial biogenesis, mitophagy flux and the UPR are activated by an acute bout of exercise. Lack of PGC-1α results in an attenuated biogenesis response to acute exercise, as well as reduced mitophagy flux, despite greater metabolic distress within the muscle. These results suggest than an acute bout of exercise is sufficient to induce mitochondrial turnover through increased biogenesis and degradation. Moreover, these two processes appear to be, at least in part, regulated by PGC-1α. While p53 appears to be important for the biogenesis response to exercise via its action on nuclear gene expression and mitochondrial localization, mitophagy signaling does not appear to be influenced by the absence of this protein. On the other hand, an important regulator of mitophagy is transcription factor EB (TFEB), as it regulates the expression of lysosomal components and other autophagy-related genes. Our results have indicated a strong correlation between the levels of TFEB and PGC-1α in muscle, supporting a co-ordinated regulation of these factors during exercise. Therefore, by investigating the interplay between PGC-1α and the autophagy-lysosome degradation machinery, we may uncover a regulatory role for the co-activator in mitochondrial turnover not only through biogenesis, but also via degradation. This suggests that PGC-1α mediates cross-talk between these two opposing processes, working to ensure mitochondrial homeostasis during muscle adaptations, not only to exercise, but also during muscle disuse, a symptom of many pathological states including cancer, aging, and obesity.

 

P. Darrell Neufer
Date
June 16, 2016 12:10
Speaker
P. Darrell Neufer   CV
Affiliation
East Carolina University, USA
Title
Bioenergetics: adaptive responses to acute exercise and exercise training
Abstract

Skeletal muscle possesses an energy conversion dynamic range of ~100-fold. This requires an exquisite integration of energetic driving forces and flux regulation within the mitochondrial oxidative phosphorylation (OXPHOS) system as well upstream biochemical pathways. The mechanisms by which OXPHOS establishes energy and redox charges throughout the cell, and how energetic driving forces respond to increases in energy demand associated with exercise and exercise training will be discussed. Maximizing efficiency of the OXPHOS system is obviously critical to exercise performance, and both calcium and phosphorylation have been implicated in maintaining cellular efficiency when metabolic demand is increased. Other factors influencing the efficiency of the OXPHOS system include flux through redox circuits that link from specific enzyme complexes, including pyruvate dehydrogenase complex and β-oxidation pathway, back to the mitochondrial inner membrane protein nicotinamide nucleotide transhydrogenase. Finally, potential strategies to manipulate mitochondrial bioenergetics as therapeutic approaches to treat disease of metabolic imbalance will be discussed. Research supported by NIH DK096907.

 

John P. Thyfault
Date
June 16, 2016 14:00
Speaker
John P. Thyfault   CV
Affiliation
University of Kansas, USA
Title
Hepatic fitness and metabolic health
Abstract

Epidemiological evidence strongly links low aerobic fitness with increased susceptibility for cancer, neurological, cardiovascular, and metabolic disease states. In contrast, individuals with high aerobic fitness are at a reduced risk for all of these diseases. Most importantly, low aerobic fitness status has proven to be the most powerful predictor of early mortality. Unfortunately, the exact mechanism(s) by which fitness status impacts disease and mortality remain largely unknown due to a number of limitations. The development of a novel, polygenic, animal model has started to provide answers. Two-way artificial selective breeding was used to create low capacity runner (LCR) and high capacity runner (HCR) strains divergent for both treadmill running capacity (run time to exhaustion) and aerobic fitness. The LCR and HCR rats display divergent intrinsic aerobic fitness despite being maintained in a sedentary condition an important feature because fitness status is dictated equally by both genetics and exercise patterns. Therefore, the HCR/LCR model allows for the examination of intrinsic aerobic fitness independent from the effects of exercise. Through a series of studies we have shown that the LCR rats are susceptible to obesity, insulin resistance, and fatty liver disease both in a chow fed and high fat fed condition while the HCR rats are protected from these conditions. The divergence in susceptibility for metabolic pathologies between the HCR and LCR is driven by multiple factors including regulation of energy intake and energy expenditure, whole body and tissue specific substrate metabolism, hepatic mitochondrial content and function, heat shock responsiveness, and transcriptional responsiveness to changes in the nutrient environment. In conclusion, aerobic fitness status impacts metabolic health through multiple whole body, cellular, and molecular mechanism(s).

Key words: obesity, fatty liver, mitochondria, insulin resistance, high fat diets, aerobic capacity

 

Thomas Solomon
Date
June 16, 2016 14:40
Speaker
Thomas Solomon   CV
Affiliation
University of Birmingham, UK
Title
Is it sufficient to simply "recommend" exercise as part of type 2 diabetes treatment?
Abstract

1Institute of Metabolism and Systems Research, College of Medicine, University of Birmingham, UK
2 School of Sport, Exercise, and Rehabilitation Sciences, College of Life and Environmental Sciences, University of Birmingham, UK


Type 2 diabetes is characterized by persistent hyperglycemia caused by insufficient pancreatic beta-cell insulin secretion to compensate for insulin resistance. Physical activity forms part of the clinical prevention and treatment recommendations for clinicians managing type 2 diabetes. This is a prudent approach since randomized controlled trials demonstrate the profound therapeutic effect of exercise on glucose disposition through improved insulin sensitivity and insulin secretory function. However, there is vast inter-individual variability in the therapeutic effect of exercise on hyperglycemia. The variability in this “exercise effectiveness” remarkably indicates that as many as 30 to 40% of patients with type 2 diabetes may not respond beneficially to the current physical activity recommendations. Such data challenges the “one size fits all” nature of the current clinical guidelines which clinicians use to treat their patients.

Exercise effectiveness on glycemic control has been associated with exercise adherence and exercise dose, and more complex phenomena such as single nucleotide polymorphisms, glucose- and lipid-lowering drugs, endocrine regulation, and prior glycemic control. This seminar will summarize these contributing factors and introduce a new concept of beta-cell glucotoxicity as a potential source of variability in exercise effectiveness in individuals with type 2 diabetes.

The inter-individual variability in the therapeutic effect of exercise on blood glucose control must not be overlooked, and future work is required to explain the sources of this variability. In the face of the ever-growing problem of type 2 diabetes and its vast impact on socioeconomics, quality of life, and mortality, it is essential that strategies are developed to maximize the optimal therapeutic benefit of exercise in all individuals, including those who would otherwise be a non-responder to traditional physical activity recommendations.

 

Paul J. Fadel
Date
June 16, 2016 15:20
Speaker
Paul J. Fadel   CV
Affiliation
University of Texas, USA
Title
Vascular consequences of physical inactivity
Abstract

Epidemiological data clearly indicate that physical inactivity and a sedentary lifestyle promotes the development of cardiovascular diseases. However, despite the known cardiovascular risk of being inactive, few studies have experimentally investigated the vascular consequences of reduced daily physical activity in humans. Indeed, previous human studies examining the vascular consequences of physical inactivity are limited and have mainly used complete removal of physical activity via bed rest or limb immobilization; extreme models of inactivity that most individuals do not experience in their daily lives. Thus, we have adopted an experimental model to examine the vascular effects of inactivity by transitioning individuals from high to low levels of ambulatory activity by eliminating any structured exercise and reducing daily step count to <5,000 steps/day. We also have begun to examine the impact of prolonged sitting on micro- and macro-vascular reactivity. The focus of the presentation will be on these recent studies identifying the early and robust deleterious impact of reduced daily activity and prolonged sitting time on vascular function.

Key words: sitting, flow mediated dilation, endothelial function, insulin resistance, microvascular reactivity

 

Ajay Chawla
Date
June 16, 2016 16:20
Speaker
Ajay Chawla   CV
Affiliation
University of California, San Francisco, USA
Title
Innate immune regulation of metabolism
Abstract

In all endotherms (warm blooded animals), the maintenance of core body temperature is essential to ensure that cellular and physiological functions operate normally under conditions of environmental challenge. In mammals, two types of programs support thermal homeostasis in cold environments: acute adaptations and acclimatization. Although programs of acclimatization are well documented across species and are of great interest to evolutionary biologists, their mechanisms, with a few exceptions (such as changes in skin pigmentation in response to sunlight or increase in oxygen carrying capacity after living at high altitudes), are largely unknown

Through our work, we have identified the mechanisms for prolonged adaptation and acclimatization to environmental cold. Unlike the acute adaptations that are initiated by the sympathetic nervous system, acclimatization to environmental cold is orchestrated by type 2 immune cells (ILC2s, eosinophils, and alternatively activated macrophages) and signals (IL-33, IL-4 and -13), which sequentially regulate the expansion, commitment, and differentiation of adipocyte precursors into beige adipocytes. Our identification of the immune system as the primary thermogenic circuit controlling the cold acclimatization process is consistent with a recent proposal that type 2 immunity coevolved as a defensive strategy against noxious environmental stimuli, of which cold might be one. These and other new findings will be presented at the meeting.