INDY as a Therapeutic Target for Cardio-Metabolic Disease

Decreased expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing citrate import into hepatocytes by different strategies can reduce hepatic triglyceride accumulation and improve hepatic insulin sensitivity, even in the absence of effects on body composition. These beneficial effects likely derive from decreased hepatic de novo fatty acid biosynthesis as a result of reduced cytoplasmic citrate levels. While in vivo and in vitro studies show that inhibition of INDY prevents intracellular lipid accumulation, body weight is not affected by organ-specific INDY inhibition. Besides these beneficial metabolic effects, INDY inhibition may also improve blood pressure control through sympathetic nervous system inhibition, partly via reduced peripheral catecholamine synthesis. These effects make INDY a promising candidate with bidirectional benefits for improving both metabolic disease and blood pressure control

Preparation for Endurance Competitions at Altitude: Physiological, Psychological, Dietary and Coaching Aspects. A Narrative Review

It was the Summer Olympic Games 1968 held in Mexico City (2,300 m) that required scientists and coaches to cope with the expected decline of performance in endurance athletes and to establish optimal preparation programs for competing at altitude. From that period until now many different recommendations for altitude acclimatization in advance of an altitude competition were proposed, ranging from several hours to several weeks. Those recommendations are mostly based on the separate consideration of the physiology of acclimatization, psychological issues, performance changes, logistical or individual aspects, but there is no review considering all these aspects in their entirety. Therefore, the present work primarily focusses on the period of altitude sojourn prior to the competition at altitude based on physiological and psychological aspects complemented by nutritional and sports practical considerations

Effects of ultramarathon running on mitochondrial function of platelets and oxidative stress parameters: a pilot study

Only a few studies have evaluated changes in mitochondrial function and oxidative stress associated with ultramarathon running. Invasive biopsies are needed to assess mitochondrial function of skeletal muscle, which may not be well tolerated by some individuals. Platelets (PLTs) as a metabolically highly active and homogenous cell population were suggested as a potentially valuable surrogate to investigate mitochondrial function. Thus, this study was aimed to evaluate mitochondrial function of PLTs and its association with individual race performance and markers of oxidative stress, muscle damage and renal dysfunction. Race performance and mitochondrial function (high-resolution respirometry, HRR) of PLTs using different substrates inducing ROUTINE, LEAK, N-pathway control state (Complex I linked oxidative phosphorylation; CI, OXPHOS), NS-pathway control state (CI + II linked OXPHOS and electron transfer pathway; ET), S-pathway control state (CII linked ET) as well as parameters of oxidative stress and antioxidant capacity, and markers of muscle and renal injury were assessed in eight male ultramarathon runners (26-45 years) before, immediately after and 24 h after an ultramarathon race (PRE, POST, and REC). Ultramarathon running induced an increase in LEAK O-2 flux of PLT mitochondria and slight, largely non-significant changes in the oxidant/antioxidant balance. Levels of creatine kinase (CK), lactate dehydrogenase (LDH), blood urea nitrogen, and creatinine were all significantly elevated POST and remained high in REC. There were inverse correlations between race time and N-linked substrate state PRE-POST, and changes in CK and LDH levels were significantly related to PLT mitochondrial LEAK and N-linked respiration PRE. Although race-related changes in respirometry parameters of PLT mitochondria were rather small, a somewhat more pronounced increase in the relative N-linked respiration in faster runners might suggest PLT CI as indicator of physical fitness. The higher PLT LEAK PRE and diminished increase of CK during the race may represent a prophylactic preconditioning and the slight but non-significant elevation of the antioxidant potential post-race as a protective consequence of the race-related oxidative stress and potential threat to the kidney. Our findings point toward an interrelationship between mitochondrial function of PLTs, individual fitness levels and extreme physical and metal stresses, which stimulates further research

Different metabolic responses during incremental exercise assessed by localized 31P MRS in sprint and endurance athletes and untrained individuals

Until recently, assessment of muscle metabolism was only possible by invasive sampling. 31P magnetic resonance spectroscopy ( 31P MRS) offers a way to study muscle metabolism non-invasively. The aim of the present study was to use spatially-resolved 31P MRS to assess the metabolism of the quadriceps muscle in sprint-trained, endurance-trained and untrained individuals during exercise and recovery. 5 sprint-trained (STA), 5 endurance-trained (ETA) and 7 untrained individuals (UTI) completed one unlocalized 31P MRS session to measure phosphocreatine (PCr) recovery, and a second session in which spatially-resolved 31P MR spectra were obtained. PCr recovery time constant (τ) was significantly longer in STA (50±17 s) and UTI (41±9 s) than in ETA (30±4 s), (P\u3c0.05). PCr changes during exercise differed between the groups, but were uniform across the different components of the quadriceps within each group. pH during recovery was higher for the ETA than for the UTI (P\u3c0.05) and also higher than for the STA (P\u3c0.01). Muscle volume was greater in STA than in UTI (P\u3c0.05) but not different from ETA. Dynamic 31P MRS revealed considerable differences among endurance and sprint athletes and untrained people. This non-invasive method offers a way to quantify differences between individual muscles and muscle components in athletes compared to untrained individuals. 2013 Georg Thieme Verlag KG Stuttgart.New York

Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

SummaryNonalcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for the metabolic syndrome and type 2 diabetes (T2D). We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD, and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver, and whole-body insulin resistance in high-fat-fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in protein kinase C epsilon (PKCε) and PKCθ activity in liver and muscle, respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver, and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of hypertriglyceridemia, NAFLD, metabolic syndrome, and T2D

Differences in Physiological Responses to Cardiopulmonary Exercise Testing in Adults With and Without Type 1 Diabetes: A Pooled Analysis

OBJECTIVE To investigate physiological responses to cardiopulmonary exercise (CPX) testing in adults with type 1 diabetes compared with age-, sex-, and BMI-matched control participants without type 1 diabetes.RESEARCH DESIGN AND METHODS We compared results from CPX tests on a cycle ergometer in individuals with type 1 diabetes and control participants without type 1 diabetes. Parameters were peak and threshold variables of VO2, heart rate, and power output. Differences between groups were investigated through restricted maximum likelihood modeling and post hoc tests. Differences between groups were explained by stepwise linear regressions (P < 0.05).RESULTS Among 303 individuals with type 1 diabetes (age 33 [interquartile range 22; 43] years, 93 females, BMI 23.6 [22; 26] kg/m2, HbA1c 6.9% [6.2; 7.7%] [52 (44; 61) mmol/mol]), VO2peak (32.55 [26.49; 38.72] vs. 42.67 ± 10.44 mL/kg/min), peak heart rate (179 [170; 187] vs. 184 [175; 191] beats/min), and peak power (216 [171; 253] vs. 245 [200; 300] W) were lower compared with 308 control participants without type 1 diabetes (all P < 0.001). Individuals with type 1 diabetes displayed an impaired degree and direction of the heart rate-to-performance curve compared with control participants without type 1 diabetes (0.07 [−0.75; 1.09] vs. 0.66 [−0.28; 1.45]; P < 0.001). None of the exercise physiological responses were associated with HbA1c in individuals with type 1 diabetes.CONCLUSIONS Individuals with type 1 diabetes show altered responses to CPX testing, which cannot be explained by HbA1c. Intriguingly, the participants in our cohort were people with recent-onset type 1 diabetes; heart rate dynamics were altered during CPX testing

Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease

Adipose tissue (commonly called body fat) can be found under the skin (subcutaneous) or around internal organs (visceral). Dysfunction of adipose tissue can cause insulin resistance and lead to excess delivery of fat to other organs such as the liver. Herein, we show that dysfunction specifically in visceral adipose tissue was associated with fatty liver disease

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery