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A Spectral Neighbor Analysis (SNAP) machine learning interatomic potential (MLIP) has been developed for simulations of carbon at extreme pressures (up to 5 TPa) and temperatures (up to 20,000 K). This was achieved using a large database of experimentally relevant quantum molecular dynamics (QMD) data, training the SNAP potential using a robust machine learning methodology, and performing extensive validation against QMD and experimental data. The resultant carbon MLIP demonstrates unprecedented accuracy and transferability in predicting the carbon phase diagram, melting curves of crystalline phases, and the shock Hugoniot, all within 3% of QMD. By achieving quantum accuracy and efficient implementation on leadership class high performance computing systems, SNAP advances frontiers of classical MD simulations by enabling atomic-scale insights at experimental time and length scales.

Reproduction and environmental stressors are generally thought to be associated with a cost to the individual experiencing them, but the physiological mechanisms mediating costs of reproduction and maternal effects remain poorly understood. Studies examining the effects of environmental stressors on a female's physiological state and body condition during reproduction, as well as physiological condition of offspring, have yielded equivocal results. Mitochondrial physiology and oxidative stress have been implicated as important mediators of life-history trade-offs. The goal of this investigation was to uncover the physiological mechanisms responsible for the enhanced trade-off between self-maintenance and offspring investment when an animal is exposed to stressful conditions during reproduction. To that end, we manipulated circulating corticosterone (CORT) levels by orally supplementing lactating female mice with CORT and investigated mitochondrial physiology and oxidative stress of both the reproductive females and their young. We found that maternal CORT exposure resulted in lower litter mass at weaning, but mitochondrial performance and oxidative status of females were not impacted. We also found potential beneficial effects of maternal CORT on mitochondrial function (e.g. higher respiratory control ratio) and oxidative stress (e.g. lower reactive oxygen species production) of offspring in adulthood, suggesting that elevated maternal CORT may be a signal for early-life adversity and prepare the organism with a predictive, adaptive response for future stressors.

The life-history patterns that animals display are a product of their ability to maximize reproductive performance while concurrently balancing numerous metabolic demands. For example, the energetic costs of reproduction may reduce an animal's ability to support self-maintenance and longevity. In this work, we evaluated the impact of parity on mitochondrial physiology in laboratory mice. The theory of mitohormesis suggests that modest exposure to reactive oxygen species can improve performance, while high levels of exposure are damaging. Following this theory, we hypothesized that females that experienced one bout of reproduction (primiparous) would display improved mitochondrial capacity and reduced oxidative damage relative to non-reproductive (nulliparous) mice, while females that had four reproductive events (multiparous) would have lower mitochondrial performance and greater oxidative damage than both nulliparous and primiparous females. We observed that multiple reproductive events enhanced the mitochondrial respiratory capacity of liver mitochondria in females with high body mass. Four-bout females showed a positive relationship between body mass and mitochondrial capacity. In contrast, non-reproductive females showed a negative relationship between body mass and mitochondrial capacity and primiparous females had a slope that did not differ from zero. Other measured variables, too, were highly dependent on body mass, suggesting that a female's body condition has strong impacts on mitochondrial physiology. We also evaluated the relationship between how much females allocated to reproduction (cumulative mass of all young weaned) and mitochondrial function and oxidative stress in the multiparous females. We found that females that allocated more to reproduction had lower basal respiration (state 4), lower mitochondrial density, and higher protein oxidation in liver mitochondria than females that allocated less. These results suggest that, at least through their first four reproductive events, female laboratory mice may experience bioenergetic benefits from reproduction but only those females that allocated the most to reproduction appear to experience a potential cost of reproduction.

Summary Nicotinamide riboside supplements (NRS) have been touted as a nutraceutical that promotes cardiometabolic and musculoskeletal health by enhancing nicotinamide adenine dinucleotide (NAD+) biosynthesis, mitochondrial function, and/or the activities of NAD-dependent sirtuin deacetylase enzymes. This investigation examined the impact of NRS on whole body energy homeostasis, skeletal muscle mitochondrial function, and corresponding shifts in the acetyl-lysine proteome, in the context of diet-induced obesity using C57BL/6NJ mice. The study also included a genetically modified mouse model that imposes greater demand on sirtuin flux and associated NAD+ consumption, specifically within muscle tissues. In general, whole body glucose control was marginally improved by NRS when administered at the midpoint of a chronic high-fat diet, but not when given as a preventative therapy upon initiation of the diet. Contrary to anticipated outcomes, the study produced little evidence that NRS increases tissue NAD+ levels, augments mitochondrial function, and/or mitigates diet-induced hyperacetylation of the skeletal muscle proteome., Graphical abstract, Highlights • Dietary NR supplementation (NRS) raises plasma and muscle NAM levels in obese mice • NRS given post obesity slightly improved glucose control and mitochondrial function • NRS did not oppose obesity-induced remodeling of the muscle acetyl-proteome • NRS during weight gain did not protect glucose control and mitochondrial function, Physiology; Proteomics; Nutrition

Silver pentazolate, a high energy density compound containing the cyclo-N

Integrins are important for mechanosensation in tissue and play, together with nutrition, a role in regulating extracellular matrix (ECM) in skeletal muscle and tendon. Integrin receptors are dimers that consist of an α and β subunit and bridge extracellular and intracellular signals. The present study investigates whether the deletion of the integrin receptor α1 subunit influences collagen and other matrix proteins in the musculotendinous tissue and whether it causes any compensatory changes in other integrin subunits in C57BL/6J mice. In addition, we study whether a high-fat diet (HFD) influences these responses in muscle or tendon. Mice on a HFD had a higher number of non-enzymatic cross-links in skeletal muscle ECM and increased gene expression of collagen and other extracellular matrix proteins. In contrast to gene expression, total collagen protein content was decreased by HFD in the muscle with no change in tendon. Integrin α1 subunit knockout resulted in a decrease of collagen type I and III, TGF-β1 and IGF-1 gene expression in muscle of HFD mice but did not affect total collagen protein compared with wild-type (WT) littermates in either muscle or tendon. There was no compensatory increase in the genes that express other integrin subunits. In conclusion, HFD induced a significant increase in expression of ECM genes in muscle. On the protein level, HFD resulted in a lower collagen content in muscle. Tendons were unaffected by the diet. Deletion of the integrin α1 subunit did not affect collagen protein or gene expression in muscle or tendon.

Coal ash spills occasionally occur due to the accidental failure of surface impoundments, and toxic metal-laden ash can pose a serious health threat to adjacent aquatic ecosystems. Here, we performed an investigation into longitudinal variations of mercury (Hg) contamination in the Dan River (North Carolina, United States) about 17 and 29 months after a February 2014 coal ash spill incident, in which the reported Hg concentrations in the spilled coal ash (210 ng/g) were 1–2 orders of magnitude higher than the river sediments (2–61 ng/g). We examined total Hg (THg) and methyl Hg (MeHg) in sediments from 0 to 65 km downstream of the spill, and found that most of the variations of THg and MeHg in surface sediments (0–16 cm) could be well accounted by the organic matter content and appeared to be not contaminated by Hg derived from coal ash. In examining MeHg bioaccumulation in invertebrates (aquatic and riparian) and fish in the Dan River and fish in a reservoir downstream of Dan River, we found no evidence of elevated MeHg bioaccumulation due to the 2014 coal ash spill. Thus, we concluded that Hg contamination from the coal ash spill is largely absent in the Dan River for both surface sediments and biota within the first three years of spill (until 2017), even though the majority of coal ash may be buried deeper in the sediment in the river channel and/or the downstream reservoir. Alternatively, the Hg associated with the coal ash is largely not bioavailable for extensive microbial Hg methylation. The findings provide useful insights into remediation strategies for this incident and other coal ash spills.

Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMPK is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high-fat (HF)–fed SkM-specific AMPKα1α2 knockout (mdKO) mice and AMPKα1α2lox/lox littermates (wild-type [WT]). Lean mdKO and WT mice were phenotypically similar. HF-fed mice were equally obese and maintained lean mass regardless of genotype. Results did not support the hypothesis that AMPK is protective during overnutrition. Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was approximately twofold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mammalian target of rapamycin (mTOR), a critical node for cell proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was normalized by insulin stimulation. Mitochondrial function was impaired in mdKO mice, but energy charge was preserved by AMP deamination. Results show a surprising reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental energetic processes in the muscle.

Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMP-activated protein kinase (AMPK) is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high fat (HF)-fed SkM-specific AMPKa1a2 knockout (mdKO) mice and AMPKa1a2lox/lox littermates (WT). Lean mdKO and WT mice were phenotypically similar. HF-fed mice were equally obese and maintained lean mass regardless of genotype. Results did not support the hypothesis that AMPK is protective during overnutrition. Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was ~two-fold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mTOR, a critical node for cell proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was normalized by insulin-stimulation. Mitochondrial function was impaired in mdKO mice, but energy charge was preserved by AMP deamination. Results show a surprising reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental energetic processes in the muscle.

This systematic review aims to evaluate all epidemiological evidence in the literature linking the effect of vitamin D supplementation to metabolic and hormonal functions in women with polycystic ovary syndrome. The literature search was performed with two databases, namely Medline/PubMed and Web of Science, until 20 May 2019 for both observational and experimental studies concerning relationships between vitamin D and polycystic ovary syndrome. A total of ten studies with randomized, double-blinded, and placebo-controlled trial design from 2008 to 2019 were selected for this review. The inclusion criteria were women 18–45 years of age with polycystic ovary syndrome and comparing the metabolic or endocrine parameters between placebo and vitamin D supplementation groups. A total of ten studies were selected for this review. We found that vitamin D supplementation had a significant effect on insulin metabolism, total serum testosterone, hirsutism, C-reactive protein, and total antioxidant capacity in women with polycystic ovary syndrome. Evidence from available randomized controlled trials suggests that patients with polycystic ovary syndrome should take vitamin D supplementation for the beneficial effect of metabolic profiles. However, future research is needed regarding the beneficial effects in women who are non-obese with polycystic ovary syndrome, as well as more studies with larger sample sizes.

The life-history patterns that animals display are a product of their ability to maximize reproductive performance while concurrently balancing numerous metabolic demands. For example, the energetic costs of reproduction may reduce an animal's ability to support self-maintenance and longevity. In this work, we evaluated the impact of parity on mitochondrial physiology in laboratory mice. The theory of mitohormesis suggests that modest exposure to reactive oxygen species can improve performance, while high levels of exposure are damaging. Following this theory, we hypothesized that females that experienced one bout of reproduction (primiparous) would display improved mitochondrial capacity and reduced oxidative damage relative to non-reproductive (nulliparous) mice, while females that had four reproductive events (multiparous) would have lower mitochondrial performance and greater oxidative damage than both nulliparous and primiparous females. We observed that multiple reproductive events enhanced the mitochondrial respiratory capacity of liver mitochondria in females with high body mass. Four-bout females showed a positive relationship between body mass and mitochondrial capacity. In contrast, non-reproductive females showed a negative relationship between body mass and mitochondrial capacity and primiparous females had a slope that did not differ from zero. Other measured variables, too, were highly dependent on body mass, suggesting that a female's body condition has strong impacts on mitochondrial physiology. We also evaluated the relationship between how much females allocated to reproduction (cumulative mass of all young weaned) and mitochondrial function and oxidative stress in the multiparous females. We found that females that allocated more to reproduction had lower basal respiration (state 4), lower mitochondrial density, and higher protein oxidation in liver mitochondria than females that allocated less. These results suggest that, at least through their first four reproductive events, female laboratory mice may experience bioenergetic benefits from reproduction but only those females that allocated the most to reproduction appear to experience a potential cost of reproduction.

Longevity plays a key role in the fitness of organisms, so understanding the processes that underlie variance in senescence has long been a focus of ecologists and evolutionary biologists. For decades, the performance and ultimate decline of mitochondria have been implicated in the demise of somatic tissue, but exactly why mitochondrial function declines as individual’s age has remained elusive. A possible source of decline that has been of intense debate is mutations to the mitochondrial DNA. There are two primary sources of such mutations: oxidative damage, which is widely discussed by ecologists interested in aging, and mitochondrial replication error, which is less familiar to most ecologists. The goal of this review is to introduce ecologists and evolutionary biologists to the concept of mitochondrial replication error and to review the current status of research on the relative importance of replication error in senescence. We conclude by detailing some of the gaps in our knowledge that currently make it difficult to deduce the relative importance of replication error in wild populations and encourage organismal biologists to consider this variable both when interpreting their results and as viable measure to include in their studies.

Integrins are important for mechanosensation in tissue and play, together with nutrition, a role in regulating extracellular matrix (ECM) in skeletal muscle and tendon. Integrin receptors are dimers that consist of an α and β subunit and bridge extracellular and intracellular signals. The present study investigates whether the deletion of the integrin receptor α

Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagen-binding integrin, α2β1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrin-linked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of β-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILKlox/lox) and muscle-specific ILK-deficient (ILKlox/loxHSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILKlox/lox and ILKlox/loxHSAcre mice. However, HF-fed ILKlox/loxHSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILKlox/lox mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILKlox/loxHSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries.

This study sought to examine the functional significance of mitochondrial protein acetylation using a double knockout (DKO) mouse model harboring muscle-specific deficits in acetyl CoA buffering and lysine deacetylation, due to genetic ablation of carnitine acetyltransferase and Sirtuin 3, respectively. DKO mice are highly susceptible to extreme hyperacetylation of the mitochondrial proteome and develop a more severe form of diet-induced insulin resistance than either single KO mouse line. However, the functional phenotype of hyperacetylated DKO mitochondria is largely normal. Of the >120 measures of respiratory function assayed, the most consistently observed traits of a markedly heightened acetyl-lysine landscape are enhanced oxygen flux in the context of fatty acid fuel and elevated rates of electron leak. In sum, the findings challenge the notion that lysine acetylation causes broad-ranging damage to mitochondrial quality and performance, and raise the possibility that acetyl-lysine turnover, rather than acetyl-lysine stoichiometry, modulates redox balance and carbon flux.

SUMMARY Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ~15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics., Graphical Abstract, In Brief Fisher-Wellman et al. use a recently developed mitochondrial diagnostics platform for deep phenotyping of heart mitochondria derived from three disparate genetic models of protein hyperacylation. Their findings oppose the notion that hyperacylation of the mitochondrial proteome leads to broad-ranging vulnerabilities in respiratory function and bioenergetics.

The extracellular matrix (ECM) is a highly-dynamic compartment that undergoes remodeling as a result of injury and repair. Over the past decade, mounting evidence in humans and rodents suggests that ECM remodeling is associated with diet-induced insulin resistance in several metabolic tissues. In addition, integrin receptors for the ECM have also been implicated in the regulation of insulin action. This review addresses what is currently known about the ECM, integrins, and insulin action in the muscle, liver, and adipose tissue. Understanding how ECM remodeling and integrin signaling regulate insulin action may aid in the development of new therapeutic targets for the treatment of insulin resistance and type 2 diabetes (T2D).

Protein hyperacetylation is associated with glucose intolerance and insulin resistance, suggesting that the enzymes regulating the acetylome play a role in this pathological process. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it is hypothesized that the dysregulation of the mitochondrial acetylation state, via genetic deletion of SIRT3, will amplify the deleterious effects of a high-fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, for the first time, that mice lacking SIRT3 exhibit increased insulin resistance due to defects in skeletal muscle glucose uptake. Permeabilized muscle fibers from HFD-fed SIRT3 knockout (KO) mice showed that tricarboxylic acid cycle substrate–based respiration is decreased while fatty acid–based respiration is increased, reflecting a fuel switch from glucose to fatty acids. Consistent with reduced muscle glucose uptake, hexokinase II (HKII) binding to the mitochondria is decreased in muscle from HFD-fed SIRT3 KO mice, suggesting decreased HKII activity. These results show that the absence of SIRT3 in HFD-fed mice causes profound impairments in insulin-stimulated muscle glucose uptake, creating an increased reliance on fatty acids. Insulin action was not impaired in the lean SIRT3 KO mice. This suggests that SIRT3 protects against dietary insulin resistance by facilitating glucose disposal and mitochondrial function.

Hepatic insulin resistance is associated with increased collagen. Integrin α1β1 is a collagen-binding receptor expressed on hepatocytes. Here, we show that expression of the α1 subunit is increased in hepatocytes isolated from high fat (HF)-fed mice. To determine whether the integrin α1 subunit protects against impairments in hepatic glucose metabolism, we analyzed glucose tolerance and insulin sensitivity in HF-fed integrin α1-null (itga1(-/-)) and wild-type (itga1(+/+)) littermates. Using the insulin clamp, we found that insulin-stimulated hepatic glucose production was suppressed by ∼50% in HF-fed itga1(+/+) mice. In contrast, it was not suppressed in HF-fed itga1(-/-) mice, indicating severe hepatic insulin resistance. This was associated with decreased hepatic insulin signaling in HF-fed itga1(-/-) mice. Interestingly, hepatic triglyceride and diglyceride contents were normalized to chow-fed levels in HF-fed itga1(-/-) mice. This indicates that hepatic steatosis is dissociated from insulin resistance in HF-fed itga1(-/-) mice. The decrease in hepatic lipid accumulation in HF-fed itga1(-/-) mice was associated with altered free fatty acid metabolism. These studies establish a role for integrin signaling in facilitating hepatic insulin action while promoting lipid accumulation in mice challenged with a HF diet.

The liver extracellular matrix (ECM) expands with high-fat (HF) feeding. This finding led us to address whether receptors for the ECM, integrins, are key to the development of diet-induced hepatic insulin resistance. Integrin-linked kinase (ILK) is a downstream integrin signaling molecule involved in multiple hepatic processes, including those related to differentiation, wound healing, and metabolism. We tested the hypothesis that deletion of ILK in mice on an HF diet would disrupt the ECM-integrin signaling axis, thereby preventing the transformation into the insulin-resistant liver. To determine the role of ILK in hepatic insulin action in vivo, male C57BL/6J ILKlox/lox mice were crossed with Albcre mice to produce a hepatocyte-specific ILK deletion (ILKlox/loxAlbcre). Results from this study show that hepatic ILK deletion has no effect on insulin action in lean mice but sensitizes the liver to insulin during the challenge of HF feeding. This effect corresponds to changes in the expression and activation of key insulin signaling pathways as well as a greater capacity for hepatic mitochondrial glucose oxidation. This demonstrates that ILK contributes to hepatic insulin resistance and highlights the previously undefined role of integrin signaling in the pathogenesis of diet-induced hepatic insulin resistance.

The NAD+-dependent deacetylase SIRT2 is unique amongst sirtuins as it is effective in the cytosol, as well as the mitochondria. Defining the role of cytosolic acetylation state in specific tissues is difficult since even physiological effects at the whole body level are unknown. We hypothesized that genetic SIRT2 knockout (KO) would lead to impaired insulin action, and that this impairment would be worsened in HF fed mice. Insulin sensitivity was tested using the hyperinsulinemic-euglycemic clamp in SIRT2 KO mice and WT littermates. SIRT2 KO mice exhibited reduced skeletal muscle insulin-induced glucose uptake compared to lean WT mice, and this impairment was exacerbated in HF SIRT2 KO mice. Liver insulin sensitivity was unaffected in lean SIRT2 KO mice. However, the insulin resistance that accompanies HF-feeding was worsened in SIRT2 KO mice. It was notable that the effects of SIRT2 KO were largely disassociated from cytosolic acetylation state, but were closely linked to acetylation state in the mitochondria. SIRT2 KO led to an increase in body weight that was due to increased food intake in HF fed mice. In summary, SIRT2 deletion in vivo reduces muscle insulin sensitivity and contributes to liver insulin resistance by a mechanism that is unrelated to cytosolic acetylation state. Mitochondrial acetylation state and changes in feeding behavior that result in increased body weight correspond to the deleterious effects of SIRT2 KO on insulin action.

Purpose: To test the influence of 1000 mg of quercetin (Q) with or without 120 mg of epigallocatechin 3-gallate (EGCG), 400 mg of isoquercetin, and 400 mg of eicosapentaenoic acid and docosahexaenoic acid (Q–EGCG) on exercise performance, muscle mitochondrial biogenesis, and changes in measures of immunity and inflammation before and after a 3-d period of heavy exertion. Methods: Trained cyclists (N = 39) were randomized to placebo (P), Q, or Q–EGCG and ingested supplements in a double- blinded fashion for 2 wk before, during, and 1 wk after a 3-d period in which subjects cycled for 3 hIdj1 at E57% Wmax. Blood, saliva, and muscle biopsy samples were collected before and after 2 wk of supplementation and immediately after the exercise bout on the third day. Blood and saliva samples were also collected 14 h after exercise. Results: Two-week supplementation resulted in a significant increase in plasma quercetin for Q and Q–EGCG and granulocyte oxidative burst activity (GOBA) in Q–EGCG. Immediately after the third exercise bout, significant decreases for C-reactive protein (CRP), and plasma interleukin 6 (IL-6) and interleukin 10 (IL-10) were measured in Q–EGCG compared with P. Granulocyte colony-stimulating factor and CRP were reduced in Q–EGCG 14 h after exercise. No group differences were measured in muscle messenger RNA expression for peroxisome proliferator-activated receptor F coactivator>, citrate synthase, or cytochrome c. Conclusions: Two-week supplementation with Q–EGCG was effective in augmenting GOBA and in countering inflammation after 3 d of heavy exertion in trained cyclists.

The accelerated metabolic demands of the working muscle cannot be met without a robust response from the liver. If not for the hepatic response, sustained exercise would be impossible. The liver stores, releases, and recycles potential energy. Exercise would result in hypoglycemia if it were not for the accelerated release of energy as glucose. The energetic demands on the liver are largely met by increased oxidation of fatty acids mobilized from adipose tissue. Adaptations immediately following exercise facilitate the replenishment of glycogen stores. Pancreatic glucagon and insulin responses orchestrate the hepatic response during and immediately following exercise. Like skeletal muscle and other physiological systems, liver adapts to repeated demands of exercise by increasing its capacity to produce energy by oxidizing fat. The ability of regular physical activity to increase fat oxidation is protective and can reverse fatty liver disease. Engaging in regular physical exercise has broad ranging positive health implications including those that improve the metabolic health of the liver.

Strain differences between naive, sucrose- and ethanol-exposed alcohol-preferring (P) and alcohol-nonpreferring (NP) rats were investigated in their consumption of ethanol, sucrose, and NaCl; chorda tympani (CT) nerve responses to sweet and salty stimuli; and gene expression in the anterior tongue of T1R3 and TRPV1/TRPV1t. Preference for 5% ethanol and 10% sucrose, CT responses to sweet stimuli, and T1R3 expression were greater in naive P rats than NP rats. The enhancement of the CT response to 0.5 M sucrose in the presence of varying ethanol concentrations (0.5–40%) in naive P rats was higher and shifted to lower ethanol concentrations than NP rats. Chronic ingestion of 5% sucrose or 5% ethanol decreased T1R3 mRNA in NP and P rats. Naive P rats also demonstrated bigger CT responses to NaCl+benzamil and greater TRPV1/TRPV1t expression. TRPV1t agonists produced biphasic effects on NaCl+benzamil CT responses, enhancing the response at low concentrations and inhibiting it at high concentrations. The concentration of a TRPV1/TRPV1t agonist (Maillard reacted peptides conjugated with galacturonic acid) that produced a maximum enhancement in the NaCl+benzamil CT response induced a decrease in NaCl intake and preference in P rats. In naive P rats and NP rats exposed to 5% ethanol in a no-choice paradigm, the biphasic TRPV1t agonist vs. NaCl+benzamil CT response profiles were higher and shifted to lower agonist concentrations than in naive NP rats. TRPV1/TRPV1t mRNA expression increased in NP rats but not in P rats exposed to 5% ethanol in a no-choice paradigm. We conclude that P and NP rats differ in T1R3 and TRPV1/TRPV1t expression and neural and behavioral responses to sweet and salty stimuli and to chronic sucrose and ethanol exposure.

Purpose: To determine the influence of 2 wk of quercetin (Q; 1000 mg·d-1) compared with placebo (P) supplementation on exercise performance and skeletal muscle mitochondrial biogenesis in untrained, young adult males (N = 26, age = 20.2 ± 0.4 yr, V·O2max = 46.3 ± 1.2 mL·kg-1·min-1). Methods: Using a randomized, crossover design with a 2-wk washout period, subjects provided blood and muscle biopsy samples presupplementation and postsupplementation periods and were given 12-min time trials on 15% graded treadmills after 60 min of moderate exercise preloads at 60% V·O2max. Results: Plasma Q levels rose significantly in Q versus P during the 2-wk supplementation period (interaction P value