Repositorio UFT :: Examinando por Autor "Castro-Sepulveda, Mauricio"

Examinando por Autor "Castro-Sepulveda, Mauricio"

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A single bout of resistance exercise triggers mitophagy, potentially involving the ejection of mitochondria in human skeletal muscle
(Wiley, 2024-09-24) Díaz-Castro, Francisco; Tuñón-Suárez, Mauro; Rivera, Patricia; Botella, Javier; Cancino, Jorge; Figueroa, Ana María; Gutiérrez, Juan; Cantin, Claudette; Deldicque, Louise; Zbinden-Foncea, Hermann; Nielsen, Joachim; Henríquez-Olguín, Carlos; Morselli, Eugenia; Castro-Sepulveda, Mauricio
Aim The present study aimed to investigate the effects of a single bout of resistance exercise on mitophagy in human skeletal muscle (SkM). Methods Eight healthy men were recruited to complete an acute bout of one-leg resistance exercise. SkM biopsies were obtained one hour after exercise in the resting leg (Rest-leg) and the contracting leg (Ex-leg). Mitophagy was assessed using protein-related abundance, transmission electron microscopy (TEM), and fluorescence microscopy. Results Our results show that acute resistance exercise increased pro-fission protein phosphorylation (DRP1Ser616) and decreased mitophagy markers such as PARKIN and BNIP3L/NIX protein abundance in the Ex-leg. Additionally, mitochondrial complex IV decreased in the Ex-leg when compared to the Rest-leg. In the Ex-leg, TEM and immunofluorescence images showed mitochondrial cristae abnormalities, a mitochondrial fission phenotype, and increased mitophagosome-like structures in both subsarcolemmal and intermyofibrillar mitochondria. We also observed increased mitophagosome-like structures on the subsarcolemmal cleft and mitochondria in the extracellular space of SkM in the Ex-leg. We stimulated human primary myotubes with CCCP, which mimics mitophagy induction in the Ex-leg, and found that BNIP3L/NIX protein abundance decreased independently of lysosomal degradation. Finally, in another human cohort, we found a negative association between BNIP3L/NIX protein abundance with both mitophagosome-like structures and mitochondrial cristae density in the SkM. Conclusion The findings suggest that a single bout of resistance exercise can initiate mitophagy, potentially involving mitochondrial ejection, in human skeletal muscle. BNIP3L/NIX is proposed as a sensitive marker for assessing mitophagy flux in SkM.
BMAL1 and CLOCK proteins exhibit differential association with mitochondrial dynamics, protein synthesis pathways and muscle strength in human muscle
(The Physiological Society, 2024-06-26) Figueroa-Toledo, A. M.; Gutiérrez-Pino, J.; Carriel-Nesvara, A.; Marchese-Bittencourt, M.; Zbinden-Foncea, Hermann; Castro-Sepulveda, Mauricio
Murine models lacking CLOCK/BMAL1 proteins in skeletal muscle (SkM) present muscle deterioration and mitochondria abnormalities. It is unclear whether humans with lower levels of these proteins in the SkM have similar alterations. Here we evaluated the association between BMAL1 and CLOCK protein mass with mitochondrial dynamics parameters and molecular and functional SkM quality markers in males. SkM biopsies were taken from the vastus lateralis of 16 male (non-athletes, non-obese and non-diabetic) subjects (8–9 a.m.). The morphology of mitochondria and their interaction with the sarcoplasmic reticulum (mitochondria-SR) were determined using transmission electron microscopy images. Additionally, protein abundance of the OXPHOS complex, mitochondria fusion/fission regulators, mitophagy and signalling proteins related to muscle protein synthesis were measured. To evaluate the quality of SkM, the cross-sectional area and maximal SkM strength were also measured. The results showed that BMAL1 protein mass was positively associated with mitochondria-SR distance, mitochondria size, mitochondria cristae density and mTOR protein mass. On the other hand, CLOCK protein mass was negatively associated with mitochondria-SR interaction, but positively associated with mitochondria complex III, OPA1 and DRP1 protein mass. Furthermore, CLOCK protein mass was positively associated with the protein synthesis signalling pathway (total mTOR, AKT and P70S6K protein mass) and SkM strength. These findings suggest that the BMAL1 and CLOCK proteins play different roles in regulating mitochondrial dynamics and SkM function in males, and that modulation of these proteins could be a potential therapeutic target for treating muscle diseases.
Cholic and deoxycholic acids induce mitochondrial dysfunction, impaired biogenesis and autophagic flux in skeletal muscle cells
(BMC, 2023-06-08) Abrigo, Johanna; Olguín, Hugo; Tacchi, Franco; Orozco-Aguilar, Josué; Valero, Mayalen; Soto, Jorge; Castro-Sepulveda, Mauricio; Elorza, Alvaro A.; Simon, Felipe; Cabello-Verrugio, Claudio
Background Skeletal muscle is sensitive to bile acids (BA) because it expresses the TGR5 receptor for BA. Cholic (CA) and deoxycholic (DCA) acids induce a sarcopenia-like phenotype through TGR5-dependent mechanisms. Besides, a mouse model of cholestasis-induced sarcopenia was characterised by increased levels of serum BA and muscle weakness, alterations that are dependent on TGR5 expression. Mitochondrial alterations, such as decreased mitochondrial potential and oxygen consumption rate (OCR), increased mitochondrial reactive oxygen species (mtROS) and unbalanced biogenesis and mitophagy, have not been studied in BA-induced sarcopenia. Methods We evaluated the effects of DCA and CA on mitochondrial alterations in C2C12 myotubes and a mouse model of cholestasis-induced sarcopenia. We measured mitochondrial mass by TOM20 levels and mitochondrial DNA; ultrastructural alterations by transmission electronic microscopy; mitochondrial biogenesis by PGC-1α plasmid reporter activity and protein levels by western blot analysis; mitophagy by the co-localisation of the MitoTracker and LysoTracker fluorescent probes; mitochondrial potential by detecting the TMRE probe signal; protein levels of OXPHOS complexes and LC3B by western blot analysis; OCR by Seahorse measures; and mtROS by MitoSOX probe signals. Results DCA and CA caused a reduction in mitochondrial mass and decreased mitochondrial biogenesis. Interestingly, DCA and CA increased LC3II/LC3I ratio and decreased autophagic flux concordant with raised mitophagosome-like structures. In addition, DCA and CA decreased mitochondrial potential and reduced protein levels in OXPHOS complexes I and II. The results also demonstrated that DCA and CA decreased basal, ATP-linked, FCCP-induced maximal respiration and spare OCR. DCA and CA also reduced the number of cristae. In addition, DCA and CA increased the mtROS. In mice with cholestasis-induced sarcopenia, TOM20, OXPHOS complexes I, II and III, and OCR were diminished. Interestingly, the OCR and OXPHOS complexes were correlated with muscle strength and bile acid levels. Conclusion Our results showed that DCA and CA decreased mitochondrial mass, possibly by reducing mitochondrial biogenesis, which affects mitochondrial function, thereby altering potential OCR and mtROS generation. Some mitochondrial alterations were also observed in a mouse model of cholestasis-induced sarcopenia characterised by increased levels of BA, such as DCA and CA.
Concurrent training and interindividual response in women with a high number of metabolic syndrome risk factors
(Frontiers Media S.A., 2022-09-22) Delgado-Floody, Pedro; Chirosa-Ríos, Luis; Caamaño-Navarrete, Felipe; Valdés-Badilla, Pablo; Herrera-Valenzuela, Tomás; Monsalves-Álvarez, Matías; Núñez-Espinosa, Cristian; Castro-Sepulveda, Mauricio; Guzmán-Muñoz, Eduardo; Andrade, David C.; Álvarez, Cristian
The non-responders (NRs) after exercise training have been poorly studied in populations with morbid obesity. The purpose of this study was to determine the NR prevalence after 20 weeks of concurrent training of morbidly obese women with a high or low number of metabolic syndrome (MetS) risk factors. Twenty-eight women with morbid obesity participated in an exercise training intervention and were allocated into two groups distributed based on a high (≥3, n = 11) or low number (<3, n = 17) of MetS risk factors. The main outcomes were waist circumference (WC), fasting plasma glucose (FPG), high-density lipids (HDL-c), triglycerides (Tg), and systolic (SBP) and diastolic (DBP) blood pressure, and secondary outcomes were body composition, anthropometric and physical fitness, determined before and after 20 weeks of concurrent training. NRs were defined as previously used technical error cut-off points for the MetS outcomes. Significantly different (all p < 0.05) prevalences of NRs between the H-MetS vs. L-MetS groups (respectively) in WC (NRs 18.2 % vs. 41.1 %, p < 0.0001), SBP (NRs 72.7 % vs. 47.0 %, p = 0.022), DBP (NRs 54.5 % vs. 76.4 %, p < 0.0001), FPG (NRs 100% vs. 64.8 %, p < 0.0001), and HDL-c (NRs 90.9 % vs. 64.7 %, p = 0.012) were observed. In addition, the H-MetS group evidenced significant changes on ΔSBP (−10.2 ± 11.4 mmHg), ΔFPG (−5.8 ± 8.2 mg/dl), ΔHDL-c (+4.0 ± 5.9 mg/dl), and ΔTg (−8.8 ± 33.8 mg/dl), all p < 0.05. The L-MetS group only showed significant changes in ΔWC (−3.8 ± 5.0 cm, p = 0.009). Comparing H-MetS vs. L-MetS groups, significant differences were observed in ∆FPG (−5.8 ± 8.2 vs. +0.3 ± 3.2 mg/dl, p = 0.027), but not in other MetS outcomes. In conclusion, 20 weeks of concurrent training promotes greater beneficial effects in morbidly obese patients with a high number of MetS risk factors. However, the NR prevalence for improving MetS outcomes was significantly superior in these more-diseased groups in SBP, FPG, and HDL-c, independent of their major training-induced effects.
Detraining’s effects on cardiorespiratory fitness and maximal and explosive strength in army soldiers: does age matter?
(MDPI, 2024-07-01) Arce-Álvarez, Alexis; Zaio, Ángelo; Salazar-Ardiles, Camila; Álvarez, Cristian; Merino-Muñoz, Pablo; Vasquez-Muñoz, Manuel; Izquierdo, Mikel; Castro-Sepulveda, Mauricio; Andrade, David C.
Purpose: This study investigated the impact of four weeks of age-dependent detraining on army soldiers’ cardiorespiratory fitness and maximal and explosive strength. Methods: Fourteen volunteer tactical athletes participated, divided into two age groups (20 to 29 and 30 to 40 years). Before and after the detraining period, we assessed their anthropometric measurements (weight, height, body mass index, fat mass, and fat-free mass), cardiorespiratory fitness (maximal oxygen uptake [VO2max] and ventilatory thresholds [VT1 and VT2]), and kinematic properties during a single-leg counter-moving jump (CMJ) test for both the dominant and non-dominant legs. Two-way ANOVA followed by the Holm–Sidak post hoc test was used. Results: The anthropometric and cardiovascular variables did not show significant differences between the groups. However, both groups exhibited a significantly reduced maximum time and speed at the VO2max. Furthermore, the flight time and maximum height during the CMJ significantly decreased in the non-dominant leg for both age groups. Notably, the dominant leg’s concentric impulse (CI) significantly reduced during the CMJ, but this effect was observed only in the 30–40 age group. There were significant differences between the two age groups. Conclusions: Our findings suggest that four weeks of detraining negatively impacts aerobic fitness and muscular strength, independently of age. However, the dominant leg may be more susceptible to detraining effects in army soldiers aged 30–40. Furthermore, as a perspective, our results strongly suggest that a detraining period could affect successful missions (aerobic performance deterioration), as well as promote a muscle imbalance between the legs, which could encourage muscle injuries and endanger combat missions.
Dietary eicosapentaenoic acid and docosahexaenoic acid for mitochondrial biogenesis and dynamics
(Elsevier, 2023-02-22) Jannas-Vela, Sebastian; Castro-Sepulveda, Mauricio
It appears that n-3 PUFA supplementation has a minimal effect on mitochondrial biogenesis in humans. However, recent studies suggest a positive effect of n-3 PUFAs on mitochondrial function and dynamics. Further studies are needed to fully understand the mechanism behind these adaptations, mainly focusing on the association between mitochondrial dynamics and mitochondrial function (e.g., bioenergetics). We hypothesize that incorporation of n-3 PUFAs into the mitochondrial membrane favors mitochondrial fusion, leading to improved mitochondrial function and enhanced skeletal muscle health.
Effects of an antioxidants cocktail on glucose metabolism at rest, during exercise, and during a glucose load in healthy young subjects
(Sociedad Chilena de Nutrición, Bromatología y Toxicología, 2023-12-15) Rodríguez, Ivan; Paez Espinosa, Enma Verónica; Zbinden-Foncea, Hermann; Echeverria, Francisca; Castro-Sepulveda, Mauricio
Background: Reactive oxygen species (ROS) regulate glucose metabolism (GM) in skeletal muscle by improving the translocation of GLUT4. Antioxidant supplementation could block this physiological effect, altering glucose signaling during exercise. However, there is limited evidence in humans on whether antioxidant intake affects GM. Therefore, we aimed to determine the effect of an antioxidant cocktail (AOC) on GM at rest and during metabolic challenges. Methods: Ten healthy male subjects received AOC supplementation (1000 mg of Vitamin C, 600 IU of Vitamin E, and 600 mg of α-lipoic acid) or placebo (2.000 mg of talc) before two trials conducted 7 days apart. Trial 1: AOC 120 and 90 minutes before an endurance exercise (EEX) bout at 60 % of maximal oxygen uptake (VO2max); Trial 2: AOC 120 and 90 minutes before an oral glucose tolerance test (OGTT; 75 g glucose). Measurements of gas exchange and capillary blood samples were collected every 15 minutes during both trials. Results: AOC supplementation increased resting glucose levels (p<0.05). During Trial 1 (EEX), the AOC increased carbohydrate oxidation (CHOox) (p= 0.03), without effect in glucose blood levels. During Trial 2 (OGTT), the AOC supplementation had no significant effect on GM parameters. Conclusion: Acute supplementation with AOC increased resting glucose levels and CHOox during EEX in healthy subjects, with no effect on GM during the OGTT.
The fasting-feeding metabolic transition regulates mitochondrial dynamics
(Federation of American Society of Experimental Biology (FASEB), 2021-10-10) Castro-Sepulveda, Mauricio; Morio, Béatrice; Tuñón-Suárez, Mauro; Jannas-Vela, Sebastian; Díaz-Castro, Francisco; Rieusset, Jennifer; Zbinden-Foncea, Hermann
In humans, insulin resistance has been linked to an impaired metabolic transition from fasting to feeding (metabolic flexibility; MetFlex). Previous studies suggest that mitochondrial dynamics response is a putative determinant of MetFlex; however, this has not been studied in humans. Thus, the aim of this study was to investigate the mitochondrial dynamics response in the metabolic transition from fasting to feeding in human peripheral blood mononuclear cells (PBMCs). Six male subjects fasted for 16 h (fasting), immediately after which they consumed a 75-g oral glucose load (glucose). In both fasting and glucose conditions, blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images. We exposed in vitro acetoacetate-treated PBMCs to the specific IP3R inhibitor Xestospongin B (XeB) to reduce IP3R-mediated mitochondrial Ca2+ accumulation. This allowed us to evaluate the role of ER-mitochondria Ca2+ exchange in the mitochondrial dynamic response to substrate availability. To determine whether PBMCs could be used in obesity context (low MetFlex), we measured mitochondrial dynamics in mouse spleen-derived lymphocytes from WT and ob/ob mice. We demonstrated that the transition from fasting to feeding reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs. In addition, we demonstrated that IP3R activity is key in the mitochondrial dynamics response when PBMCs are treated with a fasting-substrate in vitro. In murine mononuclear-cells, we confirmed that mitochondria-ER interactions are regulated in the fasted-fed transition and we further highlight mitochondria-ER miscommunication in PBMCs of diabetic mice. In conclusion, our results demonstrate that the fasting/feeding transition reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs, and that IP3R activity may potentially play a central role.
Low abundance of Mfn2 protein correlates with reduced mitochondria-SR juxtaposition and mitochondrial cristae density in human men skeletal muscle: Examining organelle measurements from TEM images
(Wiley Open Access, 2021-03-08) Castro-Sepulveda, Mauricio; Fernández-Verdejo, Rodrigo; Tuñón-Suárez, Mauro; Morales-Zúñiga, Jorge; Troncoso, Mayarling; Jannas-Vela, Sebastian; Zbinden-Foncea, Hermann
The role of mitofusin 2 (Mfn2) in the regulation of skeletal muscle (SM) mitochondria-sarcoplasmic (SR) juxtaposition, mitochondrial morphology, mitochondrial cristae density (MCD), and SM quality has not been studied in humans. In in vitro studies, whether Mfn2 increases or decreases mitochondria-SR juxtaposition remains controversial. Transmission electron microscopy (TEM) images are commonly used to measure the organelle juxtaposition, but the measurements are performed "by-hand," thus potentially leading to between-rater differences. The purposes of this study were to: (1) examine the repeatability and reproducibility of mitochondrial-SR juxtaposition measurement from TEM images of human SM between three raters with different experience and (2) compare the mitochondrial-SR juxtaposition, mitochondrial morphology, MCD (stereological-method), and SM quality (cross-sectional area [CSA] and the maximum voluntary contraction [MVC]) between subjects with high abundance (Mfn2-HA; n = 6) and low abundance (Mfn2-LA; n = 6) of Mfn2 protein. The mitochondria-SR juxtaposition had moderate repeatability and reproducibility, with the most experienced raters showing the best values. There were no differences between Mfn2-HA and Mfn2-LA groups in mitochondrial size, distance from mitochondria to SR, CSA, or MVC. Nevertheless, the Mfn2-LA group showed lower mitochondria-SR interaction, MCD, and VO2max . In conclusion, mitochondrial-SR juxtaposition measurement depends on the experience of the rater, and Mfn2 protein seems to play a role in the metabolic control of human men SM, by regulating the mitochondria-SR interaction.
Microencapsulated pomegranate peel extract induces mitochondrial complex IV activity and prevents mitochondrial cristae alteration in brown adipose tissue in mice fed on a high-fat diet
(Cambridge University Press, 2021-09-28) Echeverria, Francisca; Jimenez Patino, Paula; Castro-Sepulveda, Mauricio; Bustamante, Andres; Garcia Concha, Paula; Poblete-Aro, Carlos; Valenzuela, Rodrigo; Garcia-Diaz, Diego F.
Pomegranate peel is an agro-industrial residue obtained after fruit processing with high total polyphenol (TP) content, making it an attractive by-product for its reuse. Pomegranate peel extract (PPE) and its bioactive compounds have shown positive effects on obesity models. Effects on favouring mitochondrial biogenesis and function have also been described. However, once phenolic compounds are extracted, their stability can be affected by diverse factors. Microencapsulation could improve PPE stability, allowing its incorporation into functional foods. Nevertheless, studies on the potential biological effects of PPE microparticles (MPPE) in obesity models are lacking. This study aims to evaluate the effect of MPPE on brown adipose tissue (BAT) mitochondrial structure and function and metabolic alterations related to obesity in mice fed a high-fat diet (HFD). PPE was microencapsulated by spray drying using inulin (IN) as a wall material and physically-chemically characterised. Eight-week-old male C57BL/6J mice (n 40) were randomly distributed into five groups: control diet (CD), HFD, HFD + IN, HFD + PPE (50 mg/kg per d TP) and HFD + MPPE (50 mg/kg per d TP), for 14 weeks. A glucose tolerance test and indirect calorimetry were conducted. Blood and adipose tissue samples were obtained. MPPE supplementation prevented HFD-induced body weight gain (P < 0·001), fasting glycaemia (P = 0·007) and total cholesterol rise (P = 0·001). MPPE resulted in higher BAT mitochondrial complex IV activity (P = 0·03) and prevented HFD-induced mitochondrial cristae alteration (P = 0·02). In conclusion, MPPE prevented HFD-induced excessive body weight gain and associated metabolic disturbances, potentially by activating complex IV activity and preserving mitochondrial cristae structure in BAT in mice fed with a HFD.
Mitochondria-SR interaction and mitochondrial fusion/fission in the regulation of skeletal muscle metabolism
(Elsevier, 2023-07-01) Castro-Sepulveda, Mauricio; Fernández-Verdejo, Rodrigo; Zbinden-Foncea, Hermann; Rieusset, Jennifer
Mitochondria-endoplasmic/sarcoplasmic reticulum (ER/SR) interaction and mitochondrial fusion/fission are critical processes that influence substrate oxidation. This narrative review summarizes the evidence on the effects of substrate availability on mitochondrial-SR interaction and mitochondria fusion/fission dynamics to modulate substrate oxidation in human skeletal muscle. Evidence shows that an increase in mitochondria-SR interaction and mitochondrial fusion are associated with elevated fatty acid oxidation. In contrast, a decrease in mitochondria-SR interaction and an increase in mitochondrial fission are associated with an elevated glycolytic activity. Based on the evidence reviewed, we postulate two hypotheses for the link between mitochondrial dynamics and insulin resistance in human skeletal muscle. First, glucose and fatty acid availability modifies mitochondria-SR interaction and mitochondrial fusion/fission to help the cell to adapt substrate oxidation appropriately. Individuals with an impaired response to these substrate challenges will accumulate lipid species and develop insulin resistance in skeletal muscle. Second, a chronically elevated substrate availability (e.g. overfeeding) increases mitochondrial production of reactive oxygen species and induced mitochondrial fission. This decreases fatty acid oxidation, thus leading to the accumulation of lipid species and insulin resistance in skeletal muscle. Altogether, we propose mitochondrial dynamics as a potential target for disturbances associated with low fatty acid oxidation.
¿Los niveles de Testosterona y Cortisol influyen en el rendimiento en el rugby?: una mirada al rugby sevens
(Sociedad Chilena de Medicina del Deporte, 2022-04-30) Zúñiga-Vergara., Pedro; Castro-Sepulveda, Mauricio
Resumen: Introducción: El Rugby 7 (R7) es una rama del Rugby Unión (RU) y se caracteriza principalmente por ser un deporte de oposición con períodos de juego intensos y de corta duración, por lo tanto, los componentes psicológicos y fisiológicos juegan un rol en el rendimiento. En el R7, los deportistas compiten varias veces durante un mismo día, permitiendo la acumulación de fatiga. Esta acumulación de fatiga se puede explicar principalmente por la intensidad del juego y el número de colisiones a alta intensidad provocando perturbaciones a nivel muscular, endocrino y del sistema inmune. Sin embargo, a la fecha no existen trabajos que integren las respuestas fisiológicas como, por ejemplo, las respuestas hormonales de los jugadores a dichas demandas. Objetivo: Realizar una revisión de la literatura científica en relación al efecto de las hormonas T, C y el Ratio T/C en el rendimiento deportivo en el R7. Metodología: Revisión narrativa de la literatuta, se realizó una búsqueda durante los meses de abril a noviembre del 2021 en 4 bases de datos (Pubmed/Medline, Google Scholar, Scopus (Elsevier) y Scielo). Después de analizar 335 textos se consideró su utilidad y relevacia para la inclusión a esta revisión. 11 Estudios cumplierón con los criterios de inclusión. Resultados: Los trabajos incluidos asocián la relación hormonal con el rendimiento deportivo en el RU y R7. Se destaca la relación grande (r=0,80) de la T con el rendimiento deportivo en el RU. Conclusión: Según los estudios analizados se puede observar
Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle
(Frontiers Media S.A., 2023-06-25) Castro-Sepulveda, Mauricio; Tuñón-Suárez, Mauro; Rosales-Soto, Giovanni; Vargas-Foitzick, Ronald; Deldicque, Louise; Zbinden-Foncea, Hermann
In skeletal muscle (SkM), a reduced mitochondrial elongate phenotype is associated with several metabolic disorders like type 2 diabetes mellitus (T2DM). However, the mechanisms contributing to this reduction in mitochondrial elongate phenotype in SkM have not been fully elucidated. It has recently been shown in a SkM cell line that toll-like receptor 4 (TLR4) contributes to the regulation of mitochondrial morphology. However, this has not been investigated in human SkM. Here we found that in human SkM biopsies, TLR4 protein correlated negatively with Opa1 (pro-mitochondrial fusion protein). Moreover, the incubation of human myotubes with LPS reduced mitochondrial size and elongation and induced abnormal mitochondrial cristae, which was prevented with the co-incubation of LPS with TAK242. Finally, T2DM myotubes were found to have reduced mitochondrial elongation and mitochondrial cristae density. Mitochondrial morphology, membrane structure, and insulin-stimulated glucose uptake were restored to healthy levels in T2DM myotubes treated with TAK242. In conclusion, mitochondrial morphology and mitochondrial cristae seem to be regulated by the TLR4 pathway in human SkM. Those mitochondrial alterations might potentially contribute to insulin resistance in the SkM of patients with T2DM.
Severe COVID-19 correlates with lower mitochondrial cristae density in PBMCs and greater sitting time in humans
(Wiley; The Physiological Society and the American Physiological Society, 2022-05-27) Castro-Sepulveda, Mauricio; Tapia, German; Tuñón-Suárez, Mauro; Marambio, Hugo; Valero-Breton, Mayalen; Fernández-Verdejo, Rodrigo; Zbinden-Foncea, Hermann
An interaction between mitochondrial dynamics, physical activity levels, andCOVID-19 severity has been previously hypothesized. However, this has notbeen tested. We aimed to compare mitochondrial morphology and cristae den-sity of PBMCs between subjects with non- severe COVID- 19, subjects with se-vere COVID- 19, and healthy controls. Additionally, we compared the level ofmoderate-vigorous physical activity (MVPA) and sitting time between groups.Blood samples were taken to obtain PBMCs. Mitochondrial dynamics were as-sessed by electron microscopy images and western blot of protein that regulatemitochondrial dynamics. The International Physical Activity Questionnaire(IPAQ; short version) was used to estimate the level of MVPA and the sitting timeThe patients who develop severe COVID-19 (COVID-19++) not present altera-tions of mitochondrial size neither mitochondrial density in comparison to non-severe patients COVID- 19 (COVID- 19) and control subjects (CTRL). However,compared to CTRL, COVID- 19 and COVID-19++ groups have lower mitochon-drial cristae length, a higher proportion of abnormal mitochondrial cristae. TheCOVID-19++ group has lower number (trend) and length of mitochondrial cris-tae in comparison to COVID- 19 group. COVID- 19, but not COVID- 19++ grouphad lower Opa 1, Mfn 2 and SDHB (Complex II) proteins than CTRL group.Besides, COVID-19++ group has a higher time sitting. Our results show that lowmitochondrial cristae density, potentially due to physical inactivity, is associatedwith COVID-19 severity.
Targeting mitochondria for the prevention and treatment of nonalcoholic fatty liver disease: polyphenols as a non-pharmacological approach
(Bentham Science Publishers, 2022-11-08) Zapata, Jaime; Castro-Sepulveda, Mauricio; Soto-Alarcon, Sandra; Alvarez, Daniela; Bustamante, Andres; Villarroel, Guiselle; Gallardo, Arturo; Fernando García, Diego; Valenzuela, Rodrigo; Echeverria, Francisca
Scope: Nonalcoholic fatty liver disease (NAFLD) has a high and growing prevalence globally. Mitochondria are fundamental in regulating cell energy homeostasis. Nevertheless, mitochondria control mechanisms can be exceeded in this context of energy overload. Damaged mitochondria worsen NAFLD progression. Diet and lifestyle changes are the main recommendations for NAFLD prevention and treatment. Some polyphenols have improved mitochondrial function in different NAFLD and obesity models. Objective: The study aims to discuss the potential role of polyphenols as a nonpharmacological approach targeting mitochondria to prevent and treat NAFLD, analyzing the influence of polyphenols' chemical structure, limitations and clinical projections. Methods: In vivo and in vitro NAFLD models were considered. Study searches were performed using the following keywords: nonalcoholic fatty liver disease, liver steatosis, mitochondria, mitochondrial activity, mitochondrial dynamics, mitochondrial dysfunction, mitochondrial morphology, mitochondrial cristae, fusion, fission, polyphenols, flavonoids, anthocyanins, AND/OR bioactive compounds. Conclusion: Polyphenols are a group of diverse bioactive molecules whose bioactive effects are highly determined by their chemical structure. These bioactive compounds could offer an interesting non-pharmacological approach to preventing and treating NAFLD, regulating mitochondrial dynamics and function. Nevertheless, the mitochondria' role in subjects with NAFLD treatment is not fully elucidated. The dosage and bioavailability of these compounds should be addressed when studied.
Ursodeoxycholic acid induces sarcopenia associated with decreased protein synthesis and autophagic flux
(MBC, 2023-05-27) Orozco‐Aguilar, Josué; Franco Tacchi, Franco; Valero‐Breton, Mayalen; Castro-Sepulveda, Mauricio; Simon, Felipe; Cabello‐Verrugio, Claudio
Background Skeletal muscle generates force and movements and maintains posture. Under pathological conditions, muscle fibers suffer an imbalance in protein synthesis/degradation. This event causes muscle mass loss and decreased strength and muscle function, a syndrome known as sarcopenia. Recently, our laboratory described secondary sarcopenia in a chronic cholestatic liver disease (CCLD) mouse model. Interestingly, the administration of ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is an effective therapy for cholestatic hepatic alterations. However, the effect of UDCA on skeletal muscle mass and functionality has never been evaluated, nor the possible involved mechanisms. Methods We assessed the ability of UDCA to generate sarcopenia in C57BL6 mice and develop a sarcopenic-like phenotype in C2C12 myotubes and isolated muscle fibers. In mice, we measured muscle strength by a grip strength test, muscle mass by bioimpedance and mass for specific muscles, and physical function by a treadmill test. We also detected the fiber's diameter and content of sarcomeric proteins. In C2C12 myotubes and/or isolated muscle fibers, we determined the diameter and troponin I level to validate the cellular effect. Moreover, to evaluate possible mechanisms, we detected puromycin incorporation, p70S6K, and 4EBP1 to evaluate protein synthesis and ULK1, LC3 I, and II protein levels to determine autophagic flux. The mitophagosome-like structures were detected by transmission electron microscopy. Results UDCA induced sarcopenia in healthy mice, evidenced by decreased strength, muscle mass, and physical function, with a decline in the fiber's diameter and the troponin I protein levels. In the C2C12 myotubes, we observed that UDCA caused a reduction in the diameter and content of MHC, troponin I, puromycin incorporation, and phosphorylated forms of p70S6K and 4EBP1. Further, we detected increased levels of phosphorylated ULK1, the LC3II/LC3I ratio, and the number of mitophagosome-like structures. These data suggest that UDCA induces a sarcopenic-like phenotype with decreased protein synthesis and autophagic flux. Conclusions Our results indicate that UDCA induces sarcopenia in mice and sarcopenic-like features in C2C12 myotubes and/or isolated muscle fibers concomitantly with decreased protein synthesis and alterations in autophagic flux.

Examinando por Autor "Castro-Sepulveda, Mauricio"

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