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1.
iScience ; 27(8): 110510, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39175772

RESUMEN

The physical connection between mitochondria and endoplasmic reticulum (ER) is an essential signaling hub to ensure organelle and cellular functions. In skeletal muscle, ER-mitochondria calcium (Ca2+) signaling is crucial to maintain cellular homeostasis during physical activity. High expression of BCL2L13, a member of the BCL-2 family, was suggested as an adaptive response in endurance-trained human subjects. In adult zebrafish, we found that the loss of Bcl2l13 impairs skeletal muscle structure and function. Ca2+ signaling is altered in Bcl2l13 knockout animals and mitochondrial complexes activity is decreased. Organelle fractioning in mammalian cells shows BCL2L13 at mitochondria, ER, and mitochondria-associated membranes. ER-mitochondria contact sites number is not modified by BCL2L13 modulation, but knockdown of BCL2L13 in C2C12 cells changes cytosolic Ca2+ release and mitochondrial Ca2+ uptake. This suggests that BCL2L13 interaction with mitochondria and ER, and its role in Ca2+ signaling, contributes to proper skeletal muscle function.

2.
Acta Physiol (Oxf) ; 240(9): e14203, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39023008

RESUMEN

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.


Asunto(s)
Mitofagia , Músculo Esquelético , Humanos , Mitofagia/fisiología , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Adulto , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/ultraestructura , Entrenamiento de Fuerza , Adulto Joven , Proteínas de la Membrana/metabolismo
3.
Physiol Rep ; 12(8): e16020, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38658362

RESUMEN

Desminopathy R350P is a human myopathy that is characterized by the progressive loss of muscle fiber organization. This results in the loss of muscle size, mobility, and strength. In desminopathy, inflammation affects muscle homeostasis and repair, and contributes to progressive muscle deterioration. Mitochondria morphology was also suggested to affect desminopathy progression. Epicatechin (Epi)-a natural compound found in cacao-has been proposed to regulate inflammatory signaling and mitochondria morphology in human and animal models. Hence, we hypothesize chronic Epi consumption to improve inflammatory pathway and mitochondria morphology in the peripheral blood mononuclear cells (PBMCs) of a desminopathy R350P patient. We found that 12 weeks of Epi consumption partially restored TRL4 signaling, indicative of inflammatory signaling and mitochondria morphology in the desminopathy patient. Moreover, Epi consumption improved blood health parameters, including reduced HOMA-IR and IL-6 levels in the desminopathy patient. This indicates that Epi consumption could be a useful tool to slow disease progression in desminopathy patients.


Asunto(s)
Catequina , Leucocitos Mononucleares , Mitocondrias , Humanos , Catequina/farmacología , Catequina/administración & dosificación , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Masculino , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Distrofias Musculares/tratamiento farmacológico , Distrofias Musculares/genética , Adulto , Femenino , Inflamación/metabolismo , Inflamación/patología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiomiopatías/tratamiento farmacológico , Desmina/metabolismo , Desmina/genética
4.
Rev. chil. nutr ; 50(6)dic. 2023.
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1550796

RESUMEN

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.


Antecedentes: Las especies reactivas de oxígeno (ROS) regulan el metabolismo de la glucosa (GM) en el músculo esquelético al mejorar la translocación de GLUT4. La suplementación con antioxidantes podría bloquear este efecto fisiológico, alterando la señalización de la glucosa durante el ejercicio. Sin embargo, existe evidencia limitada en humanos sobre si la ingesta de antioxidantes afecta el GM. Por lo tanto, nuestro objetivo fue determinar el efecto de un cóctel de antioxidantes (AOC) en el GM en reposo y durante desafíos metabólicos. Métodos: Sujetos sanos (sexo masculino; n= 10) recibieron suplementos de AOC (1.000 mg de vitamina C, 600 UI de vitamina E y 600 mg de ácido α-lipoico) o placebo (2.000 mg de talco) previo a dos pruebas realizadas con 7 días de diferencia. Prueba 1: AOC 120 y 90 minutos antes de una serie de ejercicio de resistencia (EEX) al 60% del consumo máximo de oxígeno (VO2max); prueba 2: AOC 120 y 90 minutos antes de una prueba de tolerancia oral a la glucosa (OGTT; 75 g de glucosa). Se obtuvieron datos de intercambio de gaseoso y muestras de sangre capilar cada 15 minutos durante ambas pruebas. Resultados: la suplementación con AOC aumentó los niveles de glucosa en reposo (p<0,05). Durante la prueba 1 (EEX), el AOC aumentó la oxidación de carbohidratos (CHOox) (p= 0,03), sin efecto en los niveles de glucosa en sangre. Durante la prueba 2 (OGTT), la suplementación con AOC no tuvo un efecto significativo en los parámetros de GM. Conclusión: Una suplementación aguda con AOC aumentó los niveles de glucosa en reposo y la CHOox durante EEX en sujetos sanos, sin efecto sobre el GM durante la OGTT.

5.
Front Cell Dev Biol ; 11: 1212779, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37435031

RESUMEN

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.

6.
Biol Res ; 56(1): 30, 2023 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-37291645

RESUMEN

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.


Asunto(s)
Colestasis , Sarcopenia , Animales , Ratones , Sarcopenia/metabolismo , Sarcopenia/patología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Mitocondrias , Modelos Animales de Enfermedad , Colestasis/metabolismo , Colestasis/patología
7.
Biol Res ; 56(1): 28, 2023 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-37237400

RESUMEN

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.


Asunto(s)
Sarcopenia , Ratones , Animales , Sarcopenia/inducido químicamente , Sarcopenia/patología , Ácido Ursodesoxicólico/farmacología , Ácido Ursodesoxicólico/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Troponina I/metabolismo , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo
8.
Metabolism ; 144: 155578, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37164310

RESUMEN

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.


Asunto(s)
Resistencia a la Insulina , Dinámicas Mitocondriales , Humanos , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Ácidos Grasos/metabolismo , Mitocondrias Musculares/metabolismo
9.
Nutrients ; 15(6)2023 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-36986095

RESUMEN

The aim of this study was to compare the potential additional effect of chia flour, whey protein, and a placebo juice to resistance training on fat-free mass (FFM) and strength gains in untrained young men. Eighteen healthy, untrained young men underwent an 8-week whole-body resistance training program, comprising three sessions per week. Subjects were randomized into three groups that after each training session consumed: (1) 30 g whey protein concentrate containing 23 g protein (WG), (2) 50 g chia flour containing 20 g protein (CG), or (3) a placebo not containing protein (PG). Strength tests (lower- and upper-limb one repetition maximum (1 RM) tests) and body composition analyses (dual-energy X-ray absorptiometry; DXA) were performed before (PRE) and after (POST) the intervention. Resistance training increased FFM and the 1 RM for each of the strength tests similarly in the three groups. FFM increased by 2.3% in WG (p = 0.04), by 3.6% in CG (p = 0.004), and by 3.0% in PG (p = 0.002)., and 1 RM increased in the different strength tests in the three groups (p < 0.05) with no difference between PG, CG, and WG. In conclusion, neither chia flour nor whey protein supplementation elicited an enhanced effect on FFM and strength gains after an 8-week resistance training program in healthy, untrained young men consuming a habitual high protein mixed diet (>1.2 g/kg/day).


Asunto(s)
Harina , Entrenamiento de Fuerza , Masculino , Humanos , Proteína de Suero de Leche , Suplementos Dietéticos , Método Doble Ciego , Composición Corporal , Fuerza Muscular , Músculo Esquelético
10.
Curr Med Chem ; 30(26): 2977-2995, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36214303

RESUMEN

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.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Polifenoles/farmacología , Polifenoles/uso terapéutico , Polifenoles/metabolismo , Antocianinas/farmacología , Mitocondrias , Dieta , Hígado/metabolismo , Mitocondrias Hepáticas/metabolismo
11.
Biol. Res ; 56: 30-30, 2023. ilus, graf
Artículo en Inglés | LILACS | ID: biblio-1513742

RESUMEN

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.


Asunto(s)
Animales , Ratones , Colestasis/metabolismo , Colestasis/patología , Sarcopenia/metabolismo , Sarcopenia/patología , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Modelos Animales de Enfermedad , Mitocondrias
12.
Biol. Res ; 56: 28-28, 2023. ilus, graf, tab
Artículo en Inglés | LILACS | ID: biblio-1513740

RESUMEN

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.


Asunto(s)
Animales , Ratones , Sarcopenia/inducido químicamente , Sarcopenia/patología , Ácido Ursodesoxicólico/metabolismo , Ácido Ursodesoxicólico/farmacología , Músculo Esquelético/metabolismo , Troponina I/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Ratones Endogámicos C57BL
13.
Front Physiol ; 13: 934038, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36217503

RESUMEN

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.

14.
Physiol Rep ; 10(14): e15369, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35883244

RESUMEN

An interaction between mitochondrial dynamics, physical activity levels, and COVID-19 severity has been previously hypothesized. However, this has not been tested. We aimed to compare mitochondrial morphology and cristae density of PBMCs between subjects with non-severe COVID-19, subjects with severe COVID-19, and healthy controls. Additionally, we compared the level of moderate-vigorous physical activity (MVPA) and sitting time between groups. Blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images and western blot of protein that regulate mitochondrial dynamics. The International Physical Activity Questionnaire (IPAQ; short version) was used to estimate the level of MVPA and the sitting time The patients who develop severe COVID-19 (COVID-19++) not present alterations 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 mitochondrial cristae length, a higher proportion of abnormal mitochondrial cristae. The COVID-19++ group has lower number (trend) and length of mitochondrial cristae in comparison to COVID-19 group. COVID-19, but not COVID-19++ group had 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 low mitochondrial cristae density, potentially due to physical inactivity, is associated with COVID-19 severity.


Asunto(s)
COVID-19 , Sedestación , Humanos , Mitocondrias/metabolismo , Dinámicas Mitocondriales , Conducta Sedentaria
15.
Curr Med Chem ; 29(6): 1110-1123, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34923936

RESUMEN

Loss of skeletal muscle (SkM) quality is associated with different clinical conditions such as aging, diabetes, obesity, cancer, and heart failure. Nutritional research has focused on identifying naturally occurring molecules that mitigate the loss of SkM quality induced by pathology or syndrome. In this context, although few human studies have been conducted, epicatechin (Epi) is a prime candidate that may positively affect SkM quality by its potential ability to mitigate muscle mass loss. This seems to be a consequence of its antioxidant and anti-inflammatory properties and its stimulation of mitochondrial biogenesis to increase myogenic differentiation, as well as its modulation of key proteins involved in SkM structure, function, metabolism, and growth. In conclusion, the Epi could prevent, mitigate, delay, and even treat muscle-related disorders caused by aging and diseases. However, studies in humans are needed.


Asunto(s)
Catequina , Insuficiencia Cardíaca , Envejecimiento , Catequina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Músculo Esquelético/metabolismo , Biogénesis de Organelos
16.
FASEB J ; 35(10): e21891, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34569666

RESUMEN

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.


Asunto(s)
Señalización del Calcio , Ingestión de Alimentos , Ayuno/metabolismo , Leucocitos Mononucleares/metabolismo , Mitocondrias/metabolismo , Dinámicas Mitocondriales , Adulto , Animales , Glucosa/administración & dosificación , Humanos , Masculino , Ratones
17.
FASEB J ; 35(4): e21553, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33749943

RESUMEN

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.


Asunto(s)
GTP Fosfohidrolasas/metabolismo , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/metabolismo , Calcio/metabolismo , Humanos , Mitocondrias/ultraestructura , Mitocondrias Musculares/metabolismo , Membranas Mitocondriales/ultraestructura , Músculo Esquelético/ultraestructura , Retículo Sarcoplasmático/metabolismo
18.
J Sports Med Phys Fitness ; 61(1): 53-62, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32674540

RESUMEN

INTRODUCTION: The purpose of this systematic review was to analyze the effect of plyometric jump training (PJT) applied in conjunction with tapering strategies on the jump performance of team-sport athletes. EVIDENCE ACQUISITION: The meta-analysis included: 1) randomized-controlled studies that incorporated a PJT program; 2) cohorts of team-sport athletes; 3) jump performance assessments; and 4) studies that incorporated a programmed taper. A systematic search was conducted in distinct electronic databases for relevant studies. Aside from jump performance, the extracted data included characteristics of the participants, PJT, and tapering. Means and standard deviations were used to calculate the effect sizes (ES). To assess the effects of moderator variables, subgroup analyses were performed. The statistical significance level was set as P<0.05. EVIDENCE SYNTHESIS: From 7020 records initially identified, 14 studies were eligible for meta-analysis. Across all included studies, there was a moderate, significant improvement in jump performance (ES=0.73; P<0.001). Additionally, the subgroup analysis demonstrated that the duration and intensity of the taper and the volume of the PJT induced similar improvements in jump performance (P<0.01). CONCLUSIONS: In summary, PJT interventions that included a programmed taper induced significant improvements in jump performance in team-sport athletes. These effects were observed after different tapering strategies in terms of volume, taper duration, and the type of PJT prescribed.


Asunto(s)
Rendimiento Atlético , Ejercicio Pliométrico , Atletas , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Deportes de Equipo
19.
Br J Nutr ; 126(6): 825-836, 2021 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-33256858

RESUMEN

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.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Dieta Alta en Grasa , Complejo IV de Transporte de Electrones/metabolismo , Mitocondrias/efectos de los fármacos , Extractos Vegetales , Granada (Fruta) , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/prevención & control , Extractos Vegetales/farmacología , Polifenoles/farmacología , Aumento de Peso
20.
Front Bioeng Biotechnol ; 8: 565679, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33224929

RESUMEN

Electrical pulse stimulation (EPS) has been suggested to be a useful method to investigate the mechanisms underlying the adaptations of human skeletal muscle to both endurance and resistance exercise. Although different myotube stimulation protocols mimicking acute and chronic endurance exercise have been developed, no convincing protocol mimicking resistance exercise exists. Adaptations to resistance exercise mainly ensue via the Akt/mTOR pathway. Therefore, the aim of this study was to develop a high frequency EPS protocol mimicking resistance exercise both acutely (100 Hz, 15 V, 0.4 ms with 4 s rest between each contraction for 30 min) and chronically (acute EPS protocol repeated on three consecutive days) on human myotubes. Compared to control conditions, the acute EPS protocol increased the phosphorylation of AktSer473 at 0 h (+91%, p = 0.02) and 3 h (+95%, p = 0.01), and mTORSer2448 at 0 h (+93%, p = 0.03), 1 h (+129%, p = 0.01), and 3 h (+104%, p = 0.0250) post-stimulation. The phosphorylation of ERK1/2Thr202/Tyr204 was increased at 0 h (+69%, p = 0.02) and 3 h (+117%, p = 0.003) post-stimulation compared to control conditions. In addition, both S6K1Thr389 (+157%, p = 0.009) and S6Ser240/244 (+153%, p = 0.003) phosphorylation increased 1 h after EPS compared to control conditions. Chronic EPS protocol increased the phosphorylation of S6K1Thr389 1 h (+105%, p = 0.03) and 3 h (+126%, p = 0.02) and the phosphorylation of S6Ser240/244 1 h (+32%, p = 0.02) after the end of the last stimulation. In conclusion, the present work shows that human muscle cells subjected to EPS can be used as an in vitro model of acute and chronic resistance exercise.

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