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1.
Sci Total Environ ; 783: 147130, 2021 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-34088150

RESUMEN

The effects of global warming and anthropogenic disturbance force animals to migrate from lower to higher elevations to find suitable new habitats. As such migrations increase hypoxic stress on the animals, it is important to understand how plateau- and plain-dwelling animals respond to low-oxygen environments. We used comparative transcriptomics to explore the response of Neodon fuscus, Lasiopodomys brandtii, and Mus musculus skeletal muscle tissues to hypoxic conditions. Results indicate that these species have adopted different oxygen transport and energy metabolism strategies for dealing with a hypoxic environment. N. fuscus promotes oxygen transport by increasing hemoglobin synthesis and reduces the risk of thrombosis through cooperative regulation of genes, including Fga, Fgb, Alb, and Ttr; genes such as Acs16, Gpat4, and Ndufb7 are involved in regulating lipid synthesis, fatty acid ß-oxidation, hemoglobin synthesis, and electron-linked transmission, thereby maintaining a normal energy supply in hypoxic conditions. In contrast, the oxygen-carrying capacity and angiogenesis of red blood cells in L. brandtii are promoted by genes in the CYP and COL families; this species maintains its bodily energy supply by enhancing the pentose phosphate pathway and mitochondrial fatty acid synthesis pathway. However, under hypoxia, M. musculus cannot effectively transport additional oxygen; thus, its cell cycle, proliferation, and migration are somewhat affected. Given its lack of hypoxic tolerance experience, M. musculus also shows significantly reduced oxidative phosphorylation levels under hypoxic conditions. Our results suggest that the glucose capacity of M. musculus skeletal muscle does not provide sufficient energy during hypoxia; thus, we hypothesize that it supplements its bodily energy by synthesizing ketone bodies. For the first time, we describe the energy metabolism pathways of N. fuscus and L. brandtii skeletal muscle tissues under hypoxic conditions. Our findings, therefore, improve our understanding of how vertebrates thrive in high altitude and plain habitats when faced with hypoxic conditions.


Asunto(s)
Hipoxia , Transcriptoma , Animales , Arvicolinae/genética , Metabolismo Energético , Femenino , Ratones , Músculo Esquelético/metabolismo
2.
Artículo en Inglés | MEDLINE | ID: mdl-34066984

RESUMEN

The human body requires energy to function. Adenosine triphosphate (ATP) is the cellular currency for energy-requiring processes including mechanical work (i.e., exercise). ATP used by the cells is ultimately derived from the catabolism of energy substrate molecules-carbohydrates, fat, and protein. In prolonged moderate to high-intensity exercise, there is a delicate interplay between carbohydrate and fat metabolism, and this bioenergetic process is tightly regulated by numerous physiological, nutritional, and environmental factors such as exercise intensity and duration, body mass and feeding state. Carbohydrate metabolism is of critical importance during prolonged endurance-type exercise, reflecting the physiological need to regulate glucose homeostasis, assuring optimal glycogen storage, proper muscle fuelling, and delaying the onset of fatigue. Fat metabolism represents a sustainable source of energy to meet energy demands and preserve the 'limited' carbohydrate stores. Coordinated neural, hormonal and circulatory events occur during prolonged endurance-type exercise, facilitating the delivery of fatty acids from adipose tissue to the working muscle for oxidation. However, with increasing exercise intensity, fat oxidation declines and is unable to supply ATP at the rate of the exercise demand. Protein is considered a subsidiary source of energy supporting carbohydrates and fat metabolism, contributing to approximately 10% of total ATP turnover during prolonged endurance-type exercise. In this review we present an overview of substrate metabolism during prolonged endurance-type exercise and the regulatory mechanisms involved in ATP turnover to meet the energetic demands of exercise.


Asunto(s)
Carbohidratos de la Dieta , Resistencia Física , Metabolismo Energético , Ejercicio Físico , Glucógeno , Humanos , Músculo Esquelético/metabolismo
3.
Int J Mol Sci ; 22(11)2021 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-34071457

RESUMEN

Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders characterized by progressive degeneration of the nervous system. Currently, there is no disease-modifying treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue communication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is thought to be an important underlying mechanism for the advantages. Here, we reviewed studies about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival, neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which there are no adequate treatments nowadays. To date, only a few myokines have been investigated for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore, future studies are needed to discover more myokines and test their effects on NDs.


Asunto(s)
Citocinas/metabolismo , Ejercicio Físico/fisiología , Músculo Esquelético/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/fisiopatología , Animales , Humanos , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/fisiopatología , Enfermedades Neurodegenerativas/fisiopatología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología
4.
Int J Mol Sci ; 22(11)2021 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-34071589

RESUMEN

The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic and analyze the impact of the complement system on angiogenesis, we induced muscle ischemia in complement factor C3 deficient (C3-/-) and wildtype control mice by femoral artery ligation (FAL). At 24 h and 7 days after FAL, we isolated the ischemic gastrocnemius muscles and investigated them by means of (immuno-)histological analyses. C3-/- mice showed elevated ischemic damage 7 days after FAL, as evidenced by H&E staining. In addition, angiogenesis was increased in C3-/- mice, as demonstrated by increased capillary/muscle fiber ratio and increased proliferating endothelial cells (CD31+/BrdU+). Moreover, our results showed that the total number of leukocytes (CD45+) was increased in C3-/- mice, which was based on an increased number of neutrophils (MPO+), neutrophil extracellular trap formation (MPO+/CitH3+), and macrophages (CD68+) displaying a shift toward an anti-inflammatory and pro-angiogenic M2-like polarized phenotype (CD68+/MRC1+). In summary, we show that the deficiency of complement factor C3 increased neutrophil and M2-like polarized macrophage accumulation in ischemic muscle tissue, contributing to angiogenesis.


Asunto(s)
Capilares/fisiopatología , Complemento C3/deficiencia , Isquemia/fisiopatología , Leucocitos/metabolismo , Músculo Esquelético/fisiopatología , Animales , Capilares/metabolismo , Complemento C3/genética , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente/métodos , Humanos , Isquemia/genética , Activación de Macrófagos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Infiltración Neutrófila , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo
5.
Int J Mol Sci ; 22(9)2021 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-34066911

RESUMEN

Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects on skeletal muscle lipid metabolism but reduced glucose uptake, indicating impaired insulin sensitivity. Muscle PGC-1α overexpression caused lipid droplet accumulation in skeletal muscle with increased expression of the fatty acid transporter CD36, fatty acid binding protein 4, perilipin 5 and CPT1b but without significant impairment of muscle glucose uptake. Simvastatin further increased the lipid droplet accumulation in PGC-1α OE mice and stimulated muscle glucose uptake. In conclusion, the impaired muscle glucose uptake in WT mice treated with simvastatin cannot be explained by lipotoxicity. PGC-1α OE mice are protected from lipotoxicity of fatty acids and triglycerides by increased the expression of FABP4, formation of lipid droplets and increased expression of CPT1b.


Asunto(s)
Metabolismo de los Lípidos/efectos de los fármacos , Músculo Esquelético/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Simvastatina/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Antígenos CD36/genética , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferasa/metabolismo , Colesterol/sangre , Proteínas de Transporte de Ácidos Grasos/genética , Proteínas de Transporte de Ácidos Grasos/metabolismo , Ácidos Grasos/sangre , Glucosa/metabolismo , Gotas Lipídicas/efectos de los fármacos , Gotas Lipídicas/metabolismo , Lipoproteína Lipasa/metabolismo , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/ultraestructura , Tamaño de los Órganos/efectos de los fármacos , Perilipina-5/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Triglicéridos/sangre
6.
Nat Commun ; 12(1): 3292, 2021 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-34078910

RESUMEN

Autophagy regulates primary cilia formation, but the underlying mechanism is not fully understood. In this study, we identify NIMA-related kinase 9 (NEK9) as a GABARAPs-interacting protein and find that NEK9 and its LC3-interacting region (LIR) are required for primary cilia formation. Mutation in the LIR of NEK9 in mice also impairs in vivo cilia formation in the kidneys. Mechanistically, NEK9 interacts with MYH9 (also known as myosin IIA), which has been implicated in inhibiting ciliogenesis through stabilization of the actin network. MYH9 accumulates in NEK9 LIR mutant cells and mice, and depletion of MYH9 restores ciliogenesis in NEK9 LIR mutant cells. These results suggest that NEK9 regulates ciliogenesis by acting as an autophagy adaptor for MYH9. Given that the LIR in NEK9 is conserved only in land vertebrates, the acquisition of the autophagic regulation of the NEK9-MYH9 axis in ciliogenesis may have possible adaptive implications for terrestrial life.


Asunto(s)
Autofagia/genética , Cilios/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Cadenas Pesadas de Miosina/genética , Quinasas Relacionadas con NIMA/genética , Secuencia de Aminoácidos , Animales , Encéfalo/citología , Encéfalo/metabolismo , Línea Celular , Cilios/genética , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Riñón/citología , Riñón/metabolismo , Hígado/citología , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Miocardio/citología , Miocardio/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Quinasas Relacionadas con NIMA/deficiencia , Unión Proteica , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Transducción de Señal
7.
Adv Exp Med Biol ; 1269: 77-82, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966198

RESUMEN

The aim of this study was to compare muscle O2 dynamics during exercise among elderly (n = 10, age: 73 ± 3 years), middle-aged (n = 9, age: 50 ± 6 years), and young (n = 10, age: 25 ± 3 years) adults. The subjects performed ramp bicycle exercise until exhaustion. Muscle O2 saturation (SmO2) and relative changes from rest in oxygenated hemoglobin/myoglobin (∆oxy-Hb/Mb), deoxygenated hemoglobin/myoglobin (∆deoxy-Hb/Mb), and total hemoglobin concentration (∆total-Hb) were monitored continuously at the vastus lateralis muscle by near-infrared spatial resolved spectroscopy. At given absolute workloads, SmO2 and ∆oxy-Hb/Mb were significantly lower in elderly than the other groups, while ∆deoxy-Hb/Mb, ∆total-Hb, and pulmonary O2 uptake (VO2) were similar among the three groups. In contrast, there were no significant differences in muscle O2 dynamics during submaximal exercise between middle-aged and young subjects. Muscle O2 dynamics may be relatively preserved in early stages of aging, although muscle deoxygenation is enhanced in late stages of aging, probably due to reduced convective O2 supply. Moreover, change in SmO2 was significantly positively correlated with peak VO2 in the elderly, while a significant negative relationship was observed in middle-aged and young subjects. In late stages of aging, diminished peak VO2 may be caused by attenuated convective O2 transport, while reduced peak VO2 can be explained by lowered muscle O2 extraction in early stages of aging.


Asunto(s)
Hemoglobinas , Consumo de Oxígeno , Adulto , Anciano , Envejecimiento , Prueba de Esfuerzo , Tolerancia al Ejercicio , Hemoglobinas/metabolismo , Humanos , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Oxígeno/metabolismo , Adulto Joven
8.
Adv Exp Med Biol ; 1269: 83-86, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966199

RESUMEN

Continuous noninvasive monitoring of muscle oxygenation has important clinical applications for muscle disorders such as compartmentation syndrome, fibromyalgia, deep vein thrombosis, malignant hyperthermia, and the assessment of training in athletic performance. NIRS has precisely such potential and has been used to detect deep venous thrombosis, evaluate athletic performance, and assess limb reperfusion and revascularization. The aim of this study was to examine the relationship between muscle hemoglobin oxygen (HbO2) and myoglobin (MbO2) desaturation using NIRS combined with venous blood sampling and HbO2 desaturation during forearm muscle exercise. Eleven normal subjects were studied, with informed consent and an IRB-approved protocol. A NIRS sensor (INVOS4100, Somanetics, Corp.) was applied on the volar aspect of the forearm. The subjects exercised their forearm by clenching and relaxing their fist while observing the oximeter and driving the reading to specified levels from 90% to 15% (minimum possible reading). Venous blood samples were withdrawn for measurement of blood gases and oxygen saturation (IL-Co-Oximeter). RSO2 (%) vs VO2 Sat showed a two-component HbO2 desaturation suggesting representation of venous HbO2 desaturation and perhaps myoglobin oxygen (MBO2) desaturation. Subtraction of the linear venous HbO2 curve from the two-component curve suggests MbO2 desaturation at venous hemoglobin oxygen saturation of about 10-20%. Conclusions: The kinetics of desaturation during exercise revealed two components representing HbO2 and MbO2 deoxygenation. The data show that MbO2 represents approximately 40% of the NIRS signal and the balance or 60% to HbO2.


Asunto(s)
Consumo de Oxígeno , Espectroscopía Infrarroja Corta , Antebrazo , Humanos , Músculo Esquelético/metabolismo , Oximetría , Oxígeno/metabolismo
9.
Adv Exp Med Biol ; 1269: 87-93, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966200

RESUMEN

INTRODUCTION: After hematopoietic stem-cell transplantation (HSCT), patients exhibit decreased muscle strength and muscle oxygen consumption. Furthermore, total corticosteroid dose affects the reduction in muscle strength after HSCT. However, to date, no studies have investigated the relationship between corticosteroid dose and muscle oxygen consumption and saturation in these patients. The purpose of this study was to investigate the relationship between steroid dose and deoxyhemoglobin (ΔHHb) and muscle oxyhemoglobin saturation (ΔSmO2) in patients undergoing HSCT. METHODS: This study included 17 men with hematologic disease who underwent allogeneic HSCT. We evaluated ankle dorsiflexor muscle force, ΔHHb, and ΔSmO2 in skeletal muscles by near-infrared spectroscopy (NIRS) in patients before and after HSCT. RESULTS: Peak ankle dorsiflexion, ΔHHb, and ΔSmO2 decreased significantly after transplantation as compared to measurements taken before transplantation (p < 0.01). The change in peak ankle dorsiflexion from before to after HSCT was not significantly correlated with total steroid dose. However, ΔHHb and ΔSmO2 from before to after HSCT were significantly correlated with total steroid dose (p < 0.01). CONCLUSION: This study showed that higher corticosteroid doses are associated with diminished skeletal muscle O2 consumption and skeletal muscle O2 demand relative to supply. Therefore, rehabilitation staff, nurses, and physicians should take note of these findings in patients undergoing HSCT. Moreover, physiotherapists should be carefully measuring muscle oxidative metabolism on skeletal muscle when planning physical exercise in such patients.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Corticoesteroides , Humanos , Masculino , Fuerza Muscular , Músculo Esquelético/metabolismo , Consumo de Oxígeno
10.
Adv Exp Med Biol ; 1269: 101-105, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966202

RESUMEN

The primary symptom in patients with chronic heart failure (CHF) is exercise intolerance. Previous studies have reported that reduced exercise tolerance in CHF can be explained not only by cardiac output (a central factor) but also by reduced skeletal muscle aerobic capacity (a peripheral factor). Although exercise training in CHF improves exercise tolerance, few studies have evaluated the effects of exercise training on each specific central and peripheral factor in CHF. The aim of this study was to investigate the central and peripheral aerobic functions in CHF and the effects of exercise training in CHF on cardiac output and skeletal muscle deoxygenation during exercise. We assessed peak oxygen uptake (VO2) during cardiopulmonary exercise testing, peak cardiac output (CO) using noninvasive hemodynamic monitoring, and muscle oxygen saturation (SmO2) using near-infrared spectroscopy (NIRS). Patients with CHF were trained for 12 weeks and performed ramp cycling exercise until exhaustion before and after the exercise training. Peak VO2, peak CO, and SmO2 changes from rest to peak exercise (ΔSmO2) were significantly lower in CHF than those in healthy subjects. As a result of exercise training, peak oxygen uptake in patients with CHF was improved and positively associated with change in ΔSmO2. In contrast, there was no change in peak cardiac output. The results of this study indicate that both cardiac and skeletal muscle functions in patients with CHF were lower than those in healthy subjects. Further, the results suggest that the improvement of exercise capacity in patients with CHF by exercise training was related to the improved utilization of oxygen (a peripheral factor) in skeletal muscle.


Asunto(s)
Insuficiencia Cardíaca , Consumo de Oxígeno , Ejercicio Físico , Prueba de Esfuerzo , Tolerancia al Ejercicio , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/terapia , Humanos , Músculo Esquelético/metabolismo
11.
Adv Exp Med Biol ; 1269: 107-112, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966203

RESUMEN

Previous studies have reported that the reduced scattering coefficient (µs') in the vastus lateralis changes during ramp-incremental exercise due to blood volume changes or accumulation of metabolic by-products. We aimed to clarify the influences of deoxygenation and blood volume changes during exercise on µs' dynamics in subjects with various aerobic capacities. Twenty-three healthy young men participated in this study. All subjects performed a ramp-incremental cycling exercise until exhaustion and were divided into two groups: lower (Low: n = 12; peak pulmonary oxygen uptake per kg of fat-free mass (VO2peak), 54.2 ± 5.3 mL/kg/min) and higher aerobic capacity group (High: n = 11; VO2peak, 69.7 ± 5.2 mL/kg/min) by median of VO2peak. Deoxygenated hemoglobin and myoglobin concentrations (deoxy[Hb + Mb]) and total [Hb + Mb] (total[Hb + Mb]) in the vastus lateralis were monitored during the exercise by three-wavelength (760, 800, and 830 nm) time-resolved NIRS. Similarly, µs' at each wavelength was continuously monitored. With increasing exercise intensity, deoxy[Hb + Mb] and total[Hb + Mb] significantly increased in both groups, and the average values of the peak amplitudes of deoxy[Hb + Mb] and total[Hb + Mb] during exercise showed a 106.4% increase and a 17.9% increase from the start of the exercise, respectively. Furthermore, the peak amplitude of total[Hb + Mb] was significantly greater in High. Conversely, there were no changes in µs' at any wavelength during exercise and no differences between two groups, suggesting that the great deoxygenation and blood volume changes during incremental exercise have little effect on µs' dynamics.


Asunto(s)
Músculo Esquelético , Consumo de Oxígeno , Prueba de Esfuerzo , Hemodinámica , Hemoglobinas/metabolismo , Humanos , Masculino , Músculo Esquelético/metabolismo , Mioglobina/análisis , Mioglobina/metabolismo , Oxígeno/metabolismo , Espectroscopía Infrarroja Corta
12.
Adv Exp Med Biol ; 1269: 367-372, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966244

RESUMEN

Insufficient O2 delivery to, and uptake by skeletal muscle can produce mobility limitations for patients with chronic diseases. Near-infrared spectroscopy (NIRS) can be used to noninvasively quantify the balance between skeletal muscle O2 delivery and utilization during contraction. However, it is not clear how the oxygenated or deoxygenated NIRS signal should be used to assess muscle O2 changes. This issue is related to the fact that the contributions of hemoglobin (Hb) and myoglobin (Mb) cannot be distinguished. This conundrum can be resolved by quantitative analysis of experimental data by computer simulations with a mechanistic, mathematical model. Model simulations distinguish dynamic responses of the oxygenated (HbO2, MbO2) and deoxygenated (HHb, HMb) contributions to the NIRS signal components (HbMbO2, HHbMb). Simulations of muscle O2 uptake and NIRS kinetics correspond closely to published experimental data (Hernández et al., J Appl Physiol 108: 1169-1176, 2010). Simulated muscle O2 uptake and oxygenation kinetics with different blood flows indicate (1) faster O2 delivery is responsible for slower muscle oxygenation kinetics; (2) Hb and Mb contributions to the HbMbO2 are similar (40-60%); and (3) Hb and Mb contributions to the HHbMb are significantly different, 80% and 20%, respectively. The effect of slow blood flow kinetics on oxygenated Hb and Mb contributions is minimal. However, the effect on the imbalance between O2 delivery and utilization rates causes significant overshoots and undershoots of deoxygenated Hb and Mb contributions. Model analysis in combination with NIRS measurements and information on hemodynamic and microvascular distribution can help to determine the use of NIRS signal in evaluating the factors limiting exercise tolerance in health and disease states.


Asunto(s)
Mioglobina , Espectroscopía Infrarroja Corta , Ejercicio Físico , Hemodinámica , Hemoglobinas/metabolismo , Humanos , Músculo Esquelético/metabolismo , Mioglobina/análisis , Mioglobina/metabolismo , Oxígeno/metabolismo , Consumo de Oxígeno
13.
Nat Commun ; 12(1): 2717, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33976150

RESUMEN

Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising noninvasive biomarker for cell death. Here, we propose an algorithm, CelFiE, to accurately estimate the relative abundances of cell types and tissues contributing to cfDNA from epigenetic cfDNA sequencing. In contrast to previous work, CelFiE accommodates low coverage data, does not require CpG site curation, and estimates contributions from multiple unknown cell types that are not available in external reference data. In simulations, CelFiE accurately estimates known and unknown cell type proportions from low coverage and noisy cfDNA mixtures, including from cell types composing less than 1% of the total mixture. When used in two clinically-relevant situations, CelFiE correctly estimates a large placenta component in pregnant women, and an elevated skeletal muscle component in amyotrophic lateral sclerosis (ALS) patients, consistent with the occurrence of muscle wasting typical in these patients. Together, these results show how CelFiE could be a useful tool for biomarker discovery and monitoring the progression of degenerative disease.


Asunto(s)
Algoritmos , Esclerosis Amiotrófica Lateral/genética , Ácidos Nucleicos Libres de Células/genética , Metilación de ADN , Epigénesis Genética , Adulto , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/patología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores/sangre , Estudios de Casos y Controles , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/clasificación , Femenino , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Especificidad de Órganos , Embarazo , Trimestres del Embarazo/sangre , Trimestres del Embarazo/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo
14.
Nat Commun ; 12(1): 2951, 2021 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-34012031

RESUMEN

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.


Asunto(s)
Fibronectinas/metabolismo , Glicosiltransferasas/metabolismo , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/patología , Pentosiltransferasa/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Membrana Basal/metabolismo , Membrana Basal/patología , Línea Celular , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Glicosilación , Glicosiltransferasas/deficiencia , Glicosiltransferasas/genética , Humanos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofias Musculares/genética , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Distrofia Muscular Animal/genética , Mutación , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/patología , Pentosiltransferasa/deficiencia , Pentosiltransferasa/genética , Fenotipo , Pez Cebra , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genética
15.
J Agric Food Chem ; 69(22): 6214-6228, 2021 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-33950680

RESUMEN

The aim of the current study is to investigate the effects of spray dry powders of Curcuma longa containing 40% curcumin (CM-SD), as a new aqueous curcumin formula, on sarcopenia in chronic forced exercise executed 10 month old ICR mice. CM-SD (80 and 40 mg/kg) increased calf thicknesses and strengths, total body and calf protein amounts, and muscle weights in both gastrocnemius and soleus muscles. mRNA expressions regarding muscle growth and protein synthesis were induced, while those of muscle degradation significantly declined in CM-SD treatment. CM-SD decreased serum biochemical markers, lipid peroxidation, and reactive oxygen species and increased endogenous antioxidants and enzyme activities. It also reduced immunoreactive myofibers for apoptosis and oxidative stress markers but increased ATPase in myofibers. These results suggest that CM-SD can be an adjunct therapy to exercise-based remedy that prevents muscle disorders including sarcopenia by anti-apoptosis, anti-inflammation, and antioxidation-mediated modulation of gene expressions related to muscle degradation and protein synthesis.


Asunto(s)
Curcumina , Sarcopenia , Animales , Antiinflamatorios/farmacología , Antioxidantes/metabolismo , Curcumina/farmacología , Ratones , Ratones Endogámicos ICR , Músculo Esquelético/metabolismo , Estrés Oxidativo , Sarcopenia/tratamiento farmacológico , Sarcopenia/metabolismo , Sarcopenia/prevención & control
16.
Proc Biol Sci ; 288(1950): 20202895, 2021 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-33975478

RESUMEN

Muscle contraction results from force-generating cross-bridge interactions between myosin and actin. Cross-bridge cycling kinetics underlie fundamental contractile properties, such as active force production and energy utilization. Factors that influence cross-bridge kinetics at the molecular level propagate through the sarcomeres, cells and tissue to modulate whole-muscle function. Conversely, movement and changes in the muscle length can influence cross-bridge kinetics on the molecular level. Reduced, single-molecule and single-fibre experiments have shown that increasing the strain on cross-bridges may slow their cycling rate and prolong their attachment duration. However, whether these strain-dependent cycling mechanisms persist in the intact muscle tissue, which encompasses more complex organization and passive elements, remains unclear. To investigate this multi-scale relationship, we adapted traditional step-stretch protocols for use with mouse soleus muscle during isometric tetanic contractions, enabling novel estimates of length-dependent cross-bridge kinetics in the intact skeletal muscle. Compared to rates at the optimal muscle length (Lo), we found that cross-bridge detachment rates increased by approximately 20% at 90% of Lo (shorter) and decreased by approximately 20% at 110% of Lo (longer). These data indicate that cross-bridge kinetics vary with whole-muscle length during intact, isometric contraction, which could intrinsically modulate force generation and energetics, and suggests a multi-scale feedback pathway between whole-muscle function and cross-bridge activity.


Asunto(s)
Contracción Isométrica , Miosinas , Animales , Cinética , Ratones , Contracción Muscular , Músculo Esquelético/metabolismo , Miosinas/metabolismo , Sarcómeros
17.
Nat Commun ; 12(1): 2887, 2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-34001905

RESUMEN

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adiposidad/genética , Ácidos Grasos/metabolismo , Enfermedades Metabólicas/genética , Músculo Esquelético/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Regulación de la Expresión Génica , Resistencia a la Insulina/genética , Masculino , Enfermedades Metabólicas/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/genética , Obesidad/metabolismo , Oxidación-Reducción , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos
18.
Artículo en Inglés | MEDLINE | ID: mdl-33946565

RESUMEN

It has been shown that specific collagen peptides combined with resistance training (RT) improves body composition and muscle strength in elderly sarcopenic men. The main purpose of this RCT study was to investigate the efficacy of the identical specific collagen peptides combined with RT on body composition and muscle strength in middle-aged, untrained men. Furthermore, in the exploratory part of the study, these results were compared with another group that had received whey protein in addition to the RT. Ninety-seven men completed this study and participated in a 12-week RT program. They ingested 15 g of specific collagen peptides (n = 30; CP-G), placebo (n = 31; P-G), or whey protein (n = 36; WP-G) daily. Changes in fat free mass and fat mass were determined by dual-energy X-ray absorptiometry (DXA), and isometric leg strength was measured. All participants had significantly (p < 0.01) improved levels in fat free mass (ΔCP-G = 3.42 ± 2.54 kg; ΔP-G = 1.83 ± 2.09 kg; ΔWP-G = 2.27 ± 2.56 kg), fat mass (ΔCP-G = -5.28 ± 3.19 kg; ΔP-G = -3.39 ± 3.13 kg; ΔWP-G = -4.08 ± 2.80 kg) and leg strength (ΔCP-G = 163 ± 189 N; ΔP-G = 100 ± 154 N; ΔWP-G = 120 ± 233 N). The main analysis revealed a statistically significantly higher increase in fat free mass (p = 0.010) and decrease in fat mass (p = 0.023) in the CP-G compared with the P-G. The exploratory analysis showed no statistically significant differences between WP-G and CP-G or P-G, regarding changes of fat free mass and fat mass. In conclusion, specific collagen peptide supplementation combined with RT was associated with a significantly greater increase in fat free mass and a decrease in fat mass compared with placebo. RT combined with whey protein also had a positive impact on body composition, but the respective effects were more pronounced following the specific collagen peptide administration.


Asunto(s)
Músculo Esquelético , Entrenamiento de Fuerza , Anciano , Composición Corporal , Colágeno , Suplementos Dietéticos , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular , Músculo Esquelético/metabolismo , Péptidos/metabolismo
19.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806433

RESUMEN

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.


Asunto(s)
Estrés del Retículo Endoplásmico/fisiología , Músculo Esquelético/fisiopatología , Atrofia Muscular/fisiopatología , Respuesta de Proteína Desplegada/fisiología , Animales , Calcio/metabolismo , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/fisiología , Homeostasis/fisiología , Humanos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo
20.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807902

RESUMEN

Although physical exercise-induced autophagy activation has been considered a therapeutic target to enhance tissue health and extend lifespan, the effects of different exercise models on autophagy in specific metabolic tissues are not completely understood. This descriptive investigation compared the acute effects of endurance (END), exhaustive (ET), strength (ST), and concurrent (CC) physical exercise protocols on markers of autophagy, genes, and proteins in the gastrocnemius muscle, heart, and liver of mice. The animals were euthanized immediately (0 h) and six hours (6 h) after the acute exercise for the measurement of glycogen levels, mRNA expression of Prkaa1, Ppargc1a, Mtor, Ulk1, Becn1, Atg5, Map1lc3b, Sqstm1, and protein levels of Beclin 1 and ATG5. The markers of autophagy were measured by quantifying the protein levels of LC3II and Sqstm1/p62 in response to three consecutive days of intraperitoneal injections of colchicine. In summary, for gastrocnemius muscle samples, the main alterations in mRNA expressions were observed after 6 h and for the ST group, and the markers of autophagy for the CC group were increased (i.e., LC3II and Sqstm1/p62). In the heart, the Beclin 1 and ATG5 levels were downregulated for the ET group. Regarding the markers of autophagy, the Sqstm1/p62 in the heart tissue was upregulated for the END and ST groups, highlighting the beneficial effects of these exercise models. The liver protein levels of ATG5 were downregulated for the ET group. After the colchicine treatment, the liver protein levels of Sqstm1/p62 were decreased for the END and ET groups compared to the CT, ST, and CC groups. These results could be related to diabetes and obesity development or liver dysfunction improvement, demanding further investigations.


Asunto(s)
Autofagia , Regulación de la Expresión Génica , Proteínas Musculares/biosíntesis , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal , Animales , Biomarcadores/metabolismo , Masculino , Ratones
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