Abstract
Mitochondrial damage is implicated as a major contributing factor for a number of noncommunicable chronic diseases such as cardiovascular diseases, cancer, obesity, and insulin ...resistance/type 2 diabetes. Here, we discuss the role of mitochondria in maintaining cellular and whole-organism homeostasis, the mechanisms that promote mitochondrial dysfunction, and the role of this phenomenon in noncommunicable chronic diseases. We also review the state of the art regarding the preclinical evidence associated with the regulation of mitochondrial function and the development of current mitochondria-targeted therapeutics to treat noncommunicable chronic diseases. Finally, we give an integrated vision of how mitochondrial damage is implicated in these metabolic diseases.
Graphical Abstract
Graphical Abstract
The endocannabinoid system (ECS) regulates energy metabolism, has been implicated in the pathogenesis of metabolic diseases and exerts its actions mainly through the type 1 cannabinoid receptor ...(CB1). Likewise, autophagy is involved in several cellular processes. It is required for the normal development of muscle mass and metabolism, and its deregulation is associated with diseases. It is known that the CB1 regulates signaling pathways that control autophagy, however, it is currently unknown whether the ECS could regulate autophagy in the skeletal muscle of obese mice. This study aimed to investigate the role of the CB1 in regulating autophagy in skeletal muscle. We found concomitant deregulation in the ECS and autophagy markers in high-fat diet-induced obesity. In obese CB1-KO mice, the autophagy-associated protein LC3 II does not accumulate when mTOR and AMPK phosphorylation levels do not change. Acute inhibition of the CB1 with JD-5037 decreased LC3 II protein accumulation and autophagic flux. Our results suggest that the CB1 regulates autophagy in the tibialis anterior skeletal muscle in both lean and obese mice.
Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor ...family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations.
•Glucocorticoid (GC) resistance has been reported in patients with chronic diseases.•These diseases include asthma, depression, cancer and cardiovascular diseases.•GC resistance promotes a chronic ...inflammatory state.•Cellular mechanisms that alter GC receptor function are involved in GC resistance.
Glucocorticoids are involved in several responses triggered by a variety of environmental and physiological stimuli. These hormones have a wide-range of regulatory effects in organisms. Synthetic glucocorticoids are extensively used to suppress allergic, inflammatory, and immune disorders. Although glucocorticoids are highly effective for therapeutic purposes, some patients chronically treated with glucocorticoids can develop reduced glucocorticoid sensitivity or even resistance, increasing patient vulnerability to exaggerated inflammatory responses. Glucocorticoid resistance can occur in several chronic diseases, including asthma, major depression, and cardiovascular conditions. In this review, we discuss the complexity of the glucocorticoid receptor and the potential role of glucocorticoid resistance in the development of chronic diseases.
Endurance training results in diverse adaptations that lead to increased performance and health benefits. A commonly measured training response is the analysis of oxygen uptake kinetics, representing ...the demand of a determined load (speed/work) on the cardiovascular, respiratory, and metabolic systems, providing useful information for the prescription of constant load or interval-type aerobic exercise. There is evidence that during high-intensity aerobic exercise some interventions prescribe brief interval times (<1-min), which may lead to a dissociation between the load prescribed and the oxygen uptake demanded, potentially affecting training outcomes. Therefore, this review explored the time to achieve a close association between the speed/work prescribed and the oxygen uptake demanded after the onset of high-intensity aerobic exercise. The evidence assessed revealed that at least 80% of the oxygen uptake amplitude is reached when phase II of oxygen uptake kinetics is completed (1 to 2 minutes after the onset of exercise, depending on the training status). We propose that the minimum work-time during high-intensity aerobic interval training sessions should be at least 1 minute for athletes and 2 minutes for non-athletes. This suggestion could be used by coaches, physical trainers, clinicians and sports or health scientists for the prescription of high-intensity aerobic interval training.
Evidence for folate's protective effects on neural tube defects led the USA and Chile to start mandatory folic acid (FA) fortification programs, decreasing up to 50%. However, ∼30% of the population ...consuming fortified foods reach supraphysiologic serum levels. Although controversial, several epidemiological and clinical observations suggest that folate increases cancer risk, giving concern about the risks of FA supplementation. The Cancer stem cells (CSCs) model has been used to explain survival to anticancer therapies. The Notch-1 pathway plays a role in several cancers and is associated with the stemness process. Different studies show that modulation of metabolic pathways regulates stemness capacity in cancer. Supraphysiologic concentrations of FA increase the proliferation of HT-29 cells by Notch-1 activation. However, whether folate can induce a stemness-like phenotype in cancer is not known. We hypothesized that FA protects from glucose deprivation-induced cell death through Notch-1 activation. HT-29 cells were challenged with glucose deprivation at basal (20 nM) and supraphysiological (400 nM) FA and 5-MTHF concentrations. We analyzed changes in stemness-like gene expression, cell death and different energetic metabolic functions. Supraphysiological concentrations of FA increased stemness-like genes, and improved survival and oxygen consumption, inducing AMPK phosphorylation and HSP-70 protein expression. We evaluated the Notch-1 pathway using the DAPT and siRNA as inhibitors, decreasing the stemness-like gene expression and preventing the FA protection against glucose deprivation-induced cell death. Moreover, they decreased oxygen consumption and AMPK phosphorylation. These results suggest that FA protects against glucose deprivation. These effects were associated with AMPK activation, a critical metabolic mediator in nutrient consumption and availability that activates the Notch-1 pathway.
In obesity, skeletal muscle mitochondrial activity changes to cope with increased nutrient availability. Autophagy has been proposed as an essential mechanism involved in the regulation of ...mitochondrial metabolism. Still, the contribution of autophagy to mitochondrial adaptations in skeletal muscle during obesity is unknown. Here, we show that in response to high‐fat diet (HFD) feeding, distinct skeletal muscles in mice exhibit differentially regulated autophagy that may modulate mitochondrial activity. We observed that after 4 and 40 weeks of high‐fat diet feeding, OXPHOS subunits and mitochondrial DNA content increased in the oxidative soleus muscle. However, in gastrocnemius muscle, which has a mixed fiber‐type composition, the mitochondrial mass increased only after 40 weeks of HFD feeding. Interestingly, fatty acid‐supported mitochondrial respiration was enhanced in gastrocnemius, but not in soleus muscle after a 4‐week HFD feeding. This increased metabolic profile in gastrocnemius was paralleled by preserving autophagy flux, while autophagy flux in soleus was reduced. To determine the role of autophagy in this differential response, we used an autophagy‐deficient mouse model with partial deletion of Atg7 specifically in skeletal muscle (SkM‐Atg7+/− mice). We observed that Atg7 reduction resulted in diminished autophagic flux in skeletal muscle, alongside blunting the HFD‐induced increase in fatty acid‐supported mitochondrial respiration observed in gastrocnemius. Remarkably, SkM‐Atg7+/− mice did not present increased mitochondria accumulation. Altogether, our results show that HFD triggers specific mitochondrial adaptations in skeletal muscles with different fiber type compositions, and that Atg7‐mediated autophagy modulates mitochondrial respiratory capacity but not its content in response to an obesogenic diet.
Whey protein (WP) supplements have grown in popularity for exercising populations to enhance muscle protein synthesis and promote recovery. The purpose of this investigation was to examine the ...macronutrient profile, especially protein, of commonly sold protein powder brands in the Colombian (South America) sports supplement market. Eleven popular whey proteins supplements made and sold on the Colombian market were sampled and determined the humidity, ash, total carbohydrates, fat, proteins, and calories (kcal). The mean calorie content declared by product labeling was significantly lower (
p
< 0.05) than measured (labeled 349.8 ± 20.3 kcal; analyzed 368.2 ± 14.9 kcal). Carbohydrate content was higher than labeled on average (labeled 3.5 ± 6 g/100 g; analyzed 21.9 ± 12.5 g/100 g) (
p
< 0.05). The protein content on the labels showed a significantly higher content, on average, than analyzed in all samples (labeled 81.4 ± 7.4; analyzed 65.7 ± 14.1) (
p
< 0.05). These data suggest, that for brands analyzed in this research, nutrient labels may be misleading, especially regarding protein, carbohydrate, and total calorie content. Consumers should diligently read, but also learn the different product labeling; however, brands should emphasize on testing their products and add amino acid profiles to guarantee quality of their products.
β-hydroxybutyrate is the main ketone body generated by the liver under starvation. Under these conditions, it can sustain ATP levels by its oxidation in mitochondria. As mitochondria can modify its ...shape and function under different nutritional challenges, we study the chronic effects of β-hydroxybutyrate supplementation on mitochondrial morphology and function, and its relation to exercise capacity. Male C57BL/6 mice were supplemented with β-hydroxybutyrate mineral salt (3.2%) or control (CT, NaCl/KCl) for six weeks and submitted to a weekly exercise performance test. We found an increase in distance, maximal speed, and time to exhaustion at two weeks of supplementation. Fatty acid metabolism and OXPHOS subunit proteins declined at two weeks in soleus but not in tibialis anterior muscles. Oxygen consumption rate on permeabilized fibers indicated a decrease in the presence of pyruvate in the short-term treatment. Both the tibialis anterior and soleus showed decreased levels of Mitofusin 2, while electron microscopy assessment revealed a significant reduction in mitochondrial cristae shape in the tibialis anterior, while a reduction in the mitochondrial number was observed only in soleus. These results suggest that short, but not long-term, β‑hydroxybutyrate supplementation increases exercise capacity, associated with modifications in mitochondrial morphology and function in mouse skeletal muscle.
Exercise regulates lipid droplet dynamics in normal and fatty liver la Fuente, Francisco Pino-de; Quezada, Laura; Sepúlveda, Carlos ...
Biochimica et biophysica acta. Molecular and cell biology of lipids,
December 2019, 2019-12-00, 20191201, Letnik:
1864, Številka:
12
Journal Article
Recenzirano
Lipids droplets (LD) are dynamics organelles that accumulate neutral lipids during nutrient surplus. LD alternates between periods of growth and consumption through regulated processes including as ...de novo lipogenesis, lipolysis and lipophagy. The liver is a central tissue in the regulation of lipid metabolism. Non-Alcoholic Fatty Liver Diseases (NAFLD) is result of the accumulation of LD in liver. Several works have been demonstrated a positive effect of exercise on reduction of liver fat. However, the study of the exercise on liver LD dynamics is far from being understood. Here we investigated the effect of chronic exercise in the regulation of LD dynamics using a mouse model of high fat diet-induced NAFLD. Mice were fed with a high-fat diet or control diet for 12 weeks; then groups were divided into chronic exercise or sedentary for additional 8 weeks. Our results showed that exercise reduced fasting glycaemia, insulin and triacylglycerides, also liver damage. However, exercise did not affect the intrahepatic triacylglycerides levels and the number of LD but reduced their size. In addition, exercise decreased the SREBP-1c levels, without changes in lipolysis, mitochondrial proteins or autophagy/lipophagy markers. Unexpectedly in the control mice, exercise increased the number of LD, also PLIN2, SREBP-1c, FAS, ATGL, HSL and MTTP levels. Our findings show that exercise rescues the liver damage in a model of NAFLD reducing the size of LD and normalizing protein markers of de novo lipogenesis and lipolysis. Moreover, exercise increases proteins associated to LD dynamics in the control mice.
•Chronic exercise induces an increase in intrahepatic triacylglyceride levels.•Chronic exercise increases protein associated to de novo lipogenesis and lipolysis.•Chronic exercise rescues the liver damage reducing the size of lipid droplets.
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