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1.
Nat Commun ; 11(1): 4643, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938935

RESUMO

Time-restricted feeding (TRF) improves metabolism independent of dietary macronutrient composition or energy restriction. To elucidate mechanisms underpinning the effects of short-term TRF, we investigated skeletal muscle and serum metabolic and transcriptomic profiles from 11 men with overweight/obesity after TRF (8 h day-1) and extended feeding (EXF, 15 h day-1) in a randomised cross-over design (trial registration: ACTRN12617000165381). Here we show that muscle core clock gene expression was similar after both interventions. TRF increases the amplitude of oscillating muscle transcripts, but not muscle or serum metabolites. In muscle, TRF induces rhythmicity of several amino acid transporter genes and metabolites. In serum, lipids are the largest class of periodic metabolites, while the majority of phase-shifted metabolites are amino acid related. In conclusion, short-term TRF in overweight men affects the rhythmicity of serum and muscle metabolites and regulates the rhythmicity of genes controlling amino acid transport, without perturbing core clock gene expression.


Assuntos
Aminoácidos/sangue , Ritmo Circadiano/genética , Jejum , Lipídeos/sangue , Músculo Esquelético/metabolismo , Adulto , Relógios Circadianos/genética , Estudos Cross-Over , Expressão Gênica , Humanos , Metabolismo dos Lipídeos , Masculino , Músculo Esquelético/fisiologia , Sobrepeso/dietoterapia , Sobrepeso/metabolismo
3.
Nutrients ; 12(8)2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32785021

RESUMO

Old age is associated with lower physical activity levels, suboptimal protein intake, and desensitization to anabolic stimuli, predisposing for age-related muscle loss (sarcopenia). Although resistance exercise (RE) and protein supplementation partially protect against sarcopenia under controlled conditions, the efficacy of home-based, unsupervised RE (HBRE) and multi-ingredient supplementation (MIS) is largely unknown. In this randomized, placebo-controlled and double-blind trial, we examined the effects of HBRE/MIS on muscle mass, strength, and function in free-living, older men. Thirty-two sedentary men underwent twelve weeks of home-based resistance band training (3 d/week), in combination with daily intake of a novel five-nutrient supplement ('Muscle5'; M5, n = 16, 77.4 ± 2.8 y) containing whey, micellar casein, creatine, vitamin D, and omega-3 fatty acids, or an isocaloric/isonitrogenous placebo (PLA; n = 16, 74.4 ± 1.3 y), containing collagen and sunflower oil. Appendicular and total lean mass (ASM; +3%, TLM; +2%), lean mass to fat ratios (ASM/% body fat; +6%, TLM/% body fat; +5%), maximal strength (grip; +8%, leg press; +17%), and function (5-Times Sit-to-Stand time; -9%) were significantly improved in the M5 group following HBRE/MIS therapy (pre vs. post tests; p < 0.05). Fast-twitch muscle fiber cross-sectional areas of the quadriceps muscle were also significantly increased in the M5 group post intervention (Type IIa; +30.9%, Type IIx, +28.5%, p < 0.05). Sub-group analysis indicated even greater gains in total lean mass in sarcopenic individuals following HBRE/MIS therapy (TLM; +1.65 kg/+3.4%, p < 0.05). We conclude that the Muscle5 supplement is a safe, well-tolerated, and effective complement to low-intensity, home-based resistance exercise and improves lean mass, strength, and overall muscle quality in old age.


Assuntos
Composição Corporal , Suplementos Nutricionais , Força Muscular , Músculo Esquelético/fisiologia , Treinamento de Resistência , Sarcopenia/terapia , Idoso , Anabolizantes/uso terapêutico , Compartimentos de Líquidos Corporais , Caseínas/uso terapêutico , Terapia Combinada , Creatina/uso terapêutico , Método Duplo-Cego , Exercício Físico , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Masculino , Fibras Musculares de Contração Rápida , Proteínas Musculares , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Quadríceps , Sarcopenia/fisiopatologia , Autocuidado , Vitamina D/uso terapêutico , Vitaminas , Proteínas do Soro do Leite/uso terapêutico
4.
Gene ; 760: 145018, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758580

RESUMO

Protein turnover is a process that is regulated by several factors and can lead to muscle hypertrophy or atrophy. The purpose of the present study was to determine the effects of ß-hydroxy-ß-methylbutyrate free acid (HMB-FA) and eccentric resistance exercise on variables related to protein turnover in rats. Thirty-two male rats were randomly assigned into four groups of eight, including control, control-HMB, exercise, and exercise-HMB. Animals in HMB groups received 340 mg/kg/day for two weeks. Animals in the exercise groups performed one session of eccentric resistance exercise consisting of eight repetitions descending from a ladder with a slope of 80 degree, with an extra load of two times body weight (100% 1RM). Twenty-four hours after the exercise session, triceps brachii muscle and serum were collected for further analysis. Exercise and HMB-FA induced lower muscle myostatin and higher muscle Fibronectin type III domain containing 5 (FNDC5), P70-S6 kinase 1 gene expression, as well as higher serum irisin and IGF-1 concentrations. Exercise alone induced higher caspase-3 and caspase-8 gene expression while HMB-FA alone induced lower caspase 3 gene expression. HMB-FA supplement increased the effect of exercise on muscle FNDC5, myostatin, and P70-S6 kinase 1 gene expression. The interaction of exercise and HMBFA resulted in an additive effect, increasing serum irisin and IGF-1 concentrations. In conclusion, a 2-week HMB-FA supplementation paired with acute eccentric resistance exercise can positively affect some genes related to muscle protein turnover.


Assuntos
Proteínas Musculares/efeitos dos fármacos , Valeratos/farmacologia , Animais , Suplementos Nutricionais , Fibronectinas/efeitos dos fármacos , Fibronectinas/metabolismo , Genes Reguladores/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Miostatina/efeitos dos fármacos , Miostatina/metabolismo , Condicionamento Físico Animal/métodos , Ratos , Ratos Sprague-Dawley , Treinamento de Resistência/métodos , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
5.
PLoS One ; 15(8): e0236689, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785240

RESUMO

OBJECTIVE: To compare the effects of photobiomodulation therapy (PBMT) and pharmacological therapy (glucocorticoids and non-steroidal anti-inflammatory drugs) applied alone and in different combinations in mdx mice. METHODS: The animals were randomized and divided into seven experimental groups treated with placebo, PBMT, prednisone, non-steroidal anti-inflammatory drug (NSAIDs), PBMT plus prednisone and PBMT plus NSAID. Wild type animals were used as control. All treatments were performed during 14 consecutive weeks. Muscular morphology, protein expression of dystrophin and functional performance were assessed at the end of the last treatment. RESULTS: Both treatments with prednisone and PBMT applied alone or combined, were effective in preserving muscular morphology. In addition, the treatments with PBMT (p = 0.0005), PBMT plus prednisone (p = 0.0048) and PBMT plus NSAID (p = 0.0021) increased dystrophin gene expression compared to placebo-control group. However, in the functional performance the PBMT presented better results compared to glucocorticoids (p<0.0001). In contrast, the use of NSAIDs did not appear to add benefits to skeletal muscle tissue in mdx mice. CONCLUSION: We believe that the promising and optimistic results about the PBMT in skeletal muscle of mdx mice may in the future contribute to this therapy to be considered a safe alternative for patients with Duchenne Muscular Dystrophy (DMD) in a washout period (between treatment periods with glucocorticoids), allowing them to remain receiving effective and safe treatment in this period, avoiding at this way periods without administration of any treatment.


Assuntos
Distrofina/genética , Terapia com Luz de Baixa Intensidade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/efeitos da radiação , Distrofia Muscular de Duchenne/terapia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Terapia Combinada , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Glucocorticoides/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Prednisona/farmacologia
6.
Nat Commun ; 11(1): 4167, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820177

RESUMO

Muscle regeneration depends on a robust albeit transient inflammatory response. Persistent inflammation is a feature of age-related regenerative deficits, yet the underlying mechanisms are poorly understood. Here, we find inflammatory-related CC-chemokine-receptor 2 (Ccr2) expression in non-hematopoietic myogenic progenitors (MPs) during regeneration. After injury, the expression of Ccr2 in MPs corresponds to the levels of its ligands, the chemokines Ccl2, 7, and 8. We find stimulation of Ccr2-activity inhibits MP fusion and contribution to myofibers. This occurs in association with increases in MAPKp38δ/γ signaling, MyoD phosphorylation, and repression of the terminal myogenic commitment factor Myogenin. High levels of Ccr2-chemokines are a feature of regenerating aged muscle. Correspondingly, deletion of Ccr2 in MPs is necessary for proper fusion into regenerating aged muscle. Finally, opportune Ccr2 inhibition after injury enhances aged regeneration and functional recovery. These results demonstrate that inflammatory-induced activation of Ccr2 signaling in myogenic cells contributes to aged muscle regenerative decline.


Assuntos
Mediadores da Inflamação/metabolismo , Músculo Esquelético/fisiopatologia , Receptores CCR2/metabolismo , Regeneração/fisiologia , Transdução de Sinais/fisiologia , Fatores Etários , Animais , Transplante de Células/métodos , Quimiocina CCL2/metabolismo , Quimiocina CCL7/metabolismo , Quimiocina CCL8/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Desenvolvimento Muscular/genética , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Miogenina/genética , Miogenina/metabolismo , Receptores CCR2/genética , Regeneração/genética , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/metabolismo , Células Satélites de Músculo Esquelético/transplante , Transdução de Sinais/genética , Ferimentos e Lesões/genética , Ferimentos e Lesões/fisiopatologia , Ferimentos e Lesões/terapia
7.
Adv Exp Med Biol ; 1265: 153-165, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32761575

RESUMO

Severe undernutrition and famine continue to be a worldwide concern, as cases have been increasing in the past 5 years, particularly in developing countries. The occurrence of nutrient restriction (NR) during pregnancy affects fetal growth, leading to small for gestational age (SGA) or intrauterine growth restricted (IUGR) offspring. During adulthood, SGA and IUGR offspring are at a higher risk for the development of metabolic syndrome. Skeletal muscle is particularly sensitive to prenatal NR. This tissue plays an essential role in oxidation and glucose metabolism because roughly 80% of insulin-mediated glucose uptake occurs in muscle, and it represents around 40% of body weight. Alterations in myofiber number, hypertrophy and myofiber type composition, decreased protein synthesis, lower mitochondrial content and activity of oxidative enzymes, and increased accumulation of intramuscular triglycerides are among the described programming effects of maternal NR on skeletal muscle. Together, these features would add to a phenotype that is prone to insulin resistance, type 2 diabetes, obesity, and metabolic syndrome. Insights from diverse animal models (i.e. ovine, swine, and rodent) have provided valuable information regarding the molecular mechanisms behind those altered developmental pathways. Understanding those molecular signatures supports the development of efficient treatments to counteract the effects of maternal NR on skeletal muscle, and its negative implications for postnatal health.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Músculo Esquelético/embriologia , Músculo Esquelético/metabolismo , Nutrientes/deficiência , Nutrientes/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Diabetes Mellitus Tipo 2 , Feminino , Humanos , Resistência à Insulina , Síndrome Metabólica , Obesidade , Gravidez
9.
PLoS One ; 15(8): e0237097, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810864

RESUMO

Neurofibromatosis type 1 (NF1) is a genetic disorder that affects a range of tissue systems, however the associated muscle weakness and fatigability can have a profound impact on quality of life. Prior studies using the limb-specific Nf1 knockout mouse (Nf1Prx1-/-) revealed an accumulation of intramyocellular lipid (IMCL) that could be rescued by a diet supplemented with L-carnitine and enriched for medium-chain fatty acids (MCFAs). In this study we used the Nf1Prx1-/- mouse to model a range of dietary interventions designed to reduce IMCL accumulation, and analyze using other modalities including in situ muscle physiology and lipid mass spectrometry. Histological IMCL accumulation was significantly reduced by a range of treatments including L-carnitine and high MCFAs alone. A low-fat diet did not affect IMCL, but did provide improvements to muscle strength. Supplementation yielded rapid improvements in IMCL within 4 weeks, but were lost once treatment was discontinued. In situ muscle measurements were highly variable in Nf1Prx1-/- mice, attributable to the severe phenotype present in this model, with fusion of the hips and an overall small hind limb muscle size. Lipidome analysis enabled segregation of the normal and modified chow diets, and fatty acid data suggested increased muscle lipolysis with the intervention. Acylcarnitines were also affected, suggestive of a mitochondrial fatty acid oxidation disorder. These data support the theory that NF1 is a lipid storage disease that can be treated by dietary intervention, and encourages future human trials.


Assuntos
Metabolismo dos Lipídeos , Força Muscular , Músculo Esquelético/metabolismo , Neurofibromatose 1/dietoterapia , Animais , Carnitina/administração & dosagem , Carnitina/uso terapêutico , Suplementos Nutricionais , Ácidos Graxos/administração & dosagem , Ácidos Graxos/uso terapêutico , Feminino , Camundongos , Músculo Esquelético/fisiopatologia , Neurofibromatose 1/genética , Neurofibromina 1/genética
10.
PLoS One ; 15(8): e0237101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817686

RESUMO

Mutations in the genes encoding for voltage-gated sodium channels cause profound sensory disturbances and other symptoms dependent on the distribution of a particular channel subtype in different organs. Humans with the gain-of-function mutation p.Leu811Pro in SCN11A (encoding for the voltage-gated Nav1.9 channel) exhibit congenital insensitivity to pain, pruritus, self-inflicted injuries, slow healing wounds, muscle weakness, Charcot-like arthropathies, and intestinal dysmotility. As already shown, knock-in mice (Scn11a+/L799P) carrying the orthologous mutation p.Leu799Pro replicate reduced pain sensitivity and show frequent tissue lesions. In the present study we explored whether Scn11a+/L799P mice develop also pruritus, muscle weakness, and changes in gastrointestinal transit time. Furthermore, we analyzed morphological and functional differences in nerves, skeletal muscle, joints and small intestine from Scn11a+/L799P and Scn11a+/+ wild type mice. Compared to Scn11a+/+ mice, Scn11a+/L799P mice showed enhanced scratching bouts before skin lesions developed, indicating pruritus. Scn11a+/L799P mice exhibited reduced grip strength, but no disturbances in motor coordination. Skeletal muscle fiber types and joint architecture were unaltered in Scn11a+/L799P mice. Their gastrointestinal transit time was unaltered. The small intestine from Scn11a+/L799P showed a small shift towards less frequent peristaltic movements. Similar proportions of lumbar dorsal root ganglion neurons from Scn11a+/L799P and Scn11a+/+ mice were calcitonin gene-related peptide (CGRP-) positive, but isolated sciatic nerves from Scn11a+/L799P mice exhibited a significant reduction of the capsaicin-evoked release of CGRP indicating reduced neurogenic inflammation. These data indicate important Nav1.9 channel functions in several organs in both humans and mice. They support the pathophysiological relevance of increased basal activity of Nav1.9 channels for sensory abnormalities (pain and itch) and suggest resulting malfunctions of the motor system and of the gastrointestinal tract. Scn11a+/L799P mice are suitable to investigate the role of Nav1.9, and to explore the pathophysiological changes and mechanisms which develop as a consequence of Nav1.9 hyperactivity.


Assuntos
Mutação com Ganho de Função , Debilidade Muscular/genética , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Prurido/genética , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Feminino , Trânsito Gastrointestinal , Força da Mão , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Movimento , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Canal de Sódio Disparado por Voltagem NAV1.9/metabolismo , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
11.
Mol Med ; 26(1): 69, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641037

RESUMO

BACKGROUND: We previously showed that the autophagy inhibitor chloroquine (CQ) increases inflammatory cleaved caspase-1 activity in myocytes, and that caspase-1/11 is protective in sterile liver injury. However, the role of caspase-1/11 in the recovery of muscle from ischemia caused by peripheral arterial disease is unknown. We hypothesized that caspase-1/11 mediates recovery in muscle via effects on autophagy and this is modulated by CQ. METHODS: C57Bl/6 J (WT) and caspase-1/11 double-knockout (KO) mice underwent femoral artery ligation (a model of hind-limb ischemia) with or without CQ (50 mg/kg IP every 2nd day). CQ effects on autophagosome formation, microtubule associated protein 1A/1B-light chain 3 (LC3), and caspase-1 expression was measured using electron microscopy and immunofluorescence. Laser Doppler perfusion imaging documented perfusion every 7 days. After 21 days, in situ physiologic testing in tibialis anterior muscle assessed peak force contraction, and myocyte size and fibrosis was also measured. Muscle satellite cell (MuSC) oxygen consumption rate (OCR) and extracellular acidification rate was measured. Caspase-1 and glycolytic enzyme expression was detected by Western blot. RESULTS: CQ increased autophagosomes, LC3 consolidation, total caspase-1 expression and cleaved caspase-1 in muscle. Perfusion, fibrosis, myofiber regeneration, muscle contraction, MuSC fusion, OCR, ECAR and glycolytic enzyme expression was variably affected by CQ depending on presence of caspase-1/11. CQ decreased perfusion recovery, fibrosis and myofiber size in WT but not caspase-1/11KO mice. CQ diminished peak force in whole muscle, and myocyte fusion in MuSC and these effects were exacerbated in caspase-1/11KO mice. CQ reductions in maximal respiration and ATP production were reduced in caspase-1/11KO mice. Caspase-1/11KO MuSC had significant increases in protein kinase isoforms and aldolase with decreased ECAR. CONCLUSION: Caspase-1/11 signaling affects the response to ischemia in muscle and effects are variably modulated by CQ. This may be critically important for disease treated with CQ and its derivatives, including novel viral diseases (e.g. COVID-19) that are expected to affect patients with comorbidities like cardiovascular disease.


Assuntos
Caspase 1/metabolismo , Caspases Iniciadoras/metabolismo , Cloroquina/farmacologia , Infecções por Coronavirus/patologia , Isquemia/patologia , Músculo Esquelético/patologia , Pneumonia Viral/patologia , Animais , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Glicólise/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Células Musculares/metabolismo , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Neovascularização Fisiológica , Fosforilação Oxidativa , Pandemias , Doença Arterial Periférica/patologia , Pneumonia Viral/tratamento farmacológico , Regeneração , Transdução de Sinais
12.
DNA Cell Biol ; 39(8): 1449-1457, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32609007

RESUMO

Kearns-Sayre Syndrome (KSS) is a severe mitochondrial disorder involving the central nervous system, eyes, ears, skeletal muscles, and heart. The mitochondrial DNA (mtDNA) rearrangements, especially the deletions, are present in almost all KSS patients and considered as the disease-causing factor. However, the size and position of mtDNA deletions are distinct in different individuals. In this study, we report the case of a pair of Chinese twins with KSS. The twin patients revealed typical KSS clinical symptoms, including heart block, bilateral sensorineural hearing loss, progressive external ophthalmoplegia, exercise intolerance, proximal limb weakness, and endocrine disorders. Using long-range polymerase chain reactions (long-range PCR) and next-generation sequencing (NGS), the genetic features of the twin patients were investigated. A large 6600 bp mtDNA deletion, ranging from position 8702 to 15,302, was detected in both patients. To our knowledge, this kind of mtDNA deletion has never been described previously. Our study enriched the mutation spectrum of KSS and showed that NGS is a powerful tool for detecting mtDNA large variants.


Assuntos
DNA Mitocondrial/genética , Doenças em Gêmeos/genética , Síndrome de Kearns-Sayre/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Sistema Nervoso Central/patologia , Criança , Cromossomos/genética , Doenças em Gêmeos/patologia , Orelha/patologia , Olho/patologia , Deleção de Genes , Predisposição Genética para Doença , Coração/fisiopatologia , Humanos , Síndrome de Kearns-Sayre/patologia , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação/genética , Oftalmoplegia Externa Progressiva Crônica/patologia , Fenótipo
13.
Anesthesiology ; 133(2): 364-376, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32665491

RESUMO

BACKGROUND: Until recently, the mechanism for the malignant hyperthermia crisis has been attributed solely to sustained massive Ca release from the sarcoplasmic reticulum on exposure to triggering agents. This study tested the hypothesis that transient receptor potential cation (TRPC) channels are important contributors to the Ca dyshomeostasis in a mouse model relevant to malignant hyperthermia. METHODS: This study examined the mechanisms responsible for Ca dyshomeostasis in RYR1-p.G2435R mouse muscles and muscle cells using calcium and sodium ion selective microelectrodes, manganese quench of Fura2 fluorescence, and Western blots. RESULTS: RYR1-p.G2435R mouse muscle cells have chronically elevated intracellular resting calcium and sodium and rate of manganese quench (homozygous greater than heterozygous) compared with wild-type muscles. After exposure to 1-oleoyl-2-acetyl-sn-glycerol, a TRPC3/6 activator, increases in intracellular resting calcium/sodium were significantly greater in RYR1-p.G2435R muscles (from 153 ± 11 nM/10 ± 0.5 mM to 304 ± 45 nM/14.2 ± 0.7 mM in heterozygotes P < 0.001] and from 251 ± 25 nM/13.9 ± 0.5 mM to 534 ± 64 nM/20.9 ± 1.5 mM in homozygotes [P < 0.001] compared with 123 ± 3 nM/8 ± 0.1 mM to 196 ± 27 nM/9.4 ± 0.7 mM in wild type). These increases were inhibited both by simply removing extracellular Ca and by exposure to either a nonspecific (gadolinium) or a newly available, more specific pharmacologic agent (SAR7334) to block TRPC6- and TRPC3-mediated cation influx into cells. Furthermore, local pretreatment with SAR7334 partially decreased the elevation of intracellular resting calcium that is seen in RYR1-p.G2435R muscles during exposure to halothane. Western blot analysis showed that expression of TRPC3 and TRPC6 were significantly increased in RYR1-p.G2435R muscles in a gene-dose-dependent manner, supporting their being a primary molecular basis for increased sarcolemmal cation influx. CONCLUSIONS: Muscle cells in knock-in mice expressing the RYR1-p.G2435R mutation are hypersensitive to TRPC3/6 activators. This hypersensitivity can be negated with pharmacologic agents that block TRPC3/6 activity. This reinforces the working hypothesis that transient receptor potential cation channels play a critical role in causing intracellular calcium and sodium overload in malignant hyperthermia-susceptible muscle, both at rest and during the malignant hyperthermia crisis.


Assuntos
Cálcio/metabolismo , Modelos Animais de Doenças , Hipertermia Maligna/metabolismo , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6/metabolismo , Animais , Feminino , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Indanos/farmacologia , Masculino , Hipertermia Maligna/genética , Hipertermia Maligna/patologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/biossíntese , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/genética , Canal de Cátion TRPC6/antagonistas & inibidores , Canal de Cátion TRPC6/genética
14.
Anesthesiology ; 133(2): 318-331, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32667155

RESUMO

BACKGROUND: Suboptimal tissue perfusion and oxygenation during surgery may be responsible for postoperative nausea and vomiting in some patients. This trial tested the hypothesis that muscular tissue oxygen saturation-guided intraoperative care reduces postoperative nausea and vomiting. METHODS: This multicenter, pragmatic, patient- and assessor-blinded randomized controlled (1:1 ratio) trial was conducted from September 2018 to June 2019 at six teaching hospitals in four different cities in China. Nonsmoking women, 18 to 65 yr old, and having elective laparoscopic surgery involving hysterectomy (n = 800) were randomly assigned to receive either intraoperative muscular tissue oxygen saturation-guided care or usual care. The goal was to maintain muscular tissue oxygen saturation, measured at flank and on forearm, greater than baseline or 70%, whichever was higher. The primary outcome was 24-h postoperative nausea and vomiting. Secondary outcomes included nausea severity, quality of recovery, and 30-day morbidity and mortality. RESULTS: Of the 800 randomized patients (median age, 50 yr [range, 27 to 65]), 799 were assessed for the primary outcome. The below-goal muscular tissue oxygen saturation area under the curve was significantly smaller in patients receiving muscular tissue oxygen saturation-guided care (n = 400) than in those receiving usual care (n = 399; flank, 50 vs. 140% · min, P < 0.001; forearm, 53 vs. 245% · min, P < 0.001). The incidences of 24-h postoperative nausea and vomiting were 32% (127 of 400) in the muscular tissue oxygen saturation-guided care group and 36% (142 of 399) in the usual care group, which were not significantly different (risk ratio, 0.89; 95% CI, 0.73 to 1.08; P = 0.251). There were no significant between-group differences for secondary outcomes. No harm was observed throughout the study. CONCLUSIONS: In a relatively young and healthy female patient population, personalized, goal-directed, muscular tissue oxygen saturation-guided intraoperative care is effective in treating decreased muscular tissue oxygen saturation but does not reduce the incidence of 24-h posthysterectomy nausea and vomiting.


Assuntos
Histerectomia/efeitos adversos , Cuidados Intraoperatórios/métodos , Músculo Esquelético/metabolismo , Consumo de Oxigênio/fisiologia , Náusea e Vômito Pós-Operatórios/metabolismo , Náusea e Vômito Pós-Operatórios/prevenção & controle , Adulto , Método Duplo-Cego , Feminino , Humanos , Histerectomia/tendências , Cuidados Intraoperatórios/tendências , Pessoa de Meia-Idade , Náusea e Vômito Pós-Operatórios/diagnóstico
15.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32630032

RESUMO

Obesity is a characteristic of COVID-19 patients and the risk of malnutrition can be underestimated due to excess of fat: a paradoxical danger. Long ICU hospitalization exposes patients to a high risk of wasting and loss of lean body mass. The complex management precludes the detection of anthropometric parameters for the definition and monitoring of the nutritional status. The use of imaging diagnostics for body composition could help to recognize and treat patients at increased risk of wasting with targeted pathways. COVID-19 patients admitted to the ICU underwent computed tomography within 24 hours and about 20 days later, to evaluate the parameters of the body and liver composition. The main results were the loss of the lean mass index and a greater increase in liver attenuation in obese subjects. These could be co-caused by COVID-19, prolonged bed rest, the complex medical nutritional therapy, and the starting condition of low-grade inflammation of the obese. The assessment of nutritional status, with body composition applied to imaging diagnostics and metabolic profiles in COVID-19, will assist in prescribing appropriate medical nutritional therapy. This will reduce recovery times and complications caused by frailty.


Assuntos
Caquexia , Infecções por Coronavirus/patologia , Obesidade/patologia , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Composição Corporal , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Estado Nutricional , Obesidade/complicações , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Estudos Prospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X
16.
Nat Commun ; 11(1): 3405, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636378

RESUMO

Omecamtiv mecarbil (OM) is a putative positive inotropic tool for treatment of systolic heart dysfunction, based on the finding that in vivo it increases the ejection fraction and in vitro it prolongs the actin-bond life time of the cardiac and slow-skeletal muscle isoforms of myosin. OM action in situ, however, is still poorly understood as the enhanced Ca2+-sensitivity of the myofilaments is at odds with the reduction of force and rate of force development observed at saturating Ca2+. Here we show, by combining fast sarcomere-level mechanics and ATPase measurements in single slow demembranated fibres from rabbit soleus, that the depressant effect of OM on the force per attached motor is reversed, without effect on the ATPase rate, by physiological concentrations of inorganic phosphate (Pi) (1-10 mM). This mechanism could underpin an energetically efficient reduction of systolic tension cost in OM-treated patients, whenever [Pi] increases with heart-beat frequency.


Assuntos
Miosinas Cardíacas/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miosinas/metabolismo , Fosfatos/farmacologia , Ureia/análogos & derivados , Adenosina Trifosfatases/metabolismo , Animais , Cálcio/metabolismo , Sinergismo Farmacológico , Masculino , Músculo Esquelético/metabolismo , Coelhos , Sarcômeros/metabolismo , Estresse Mecânico , Ureia/farmacologia
17.
Nat Commun ; 11(1): 3711, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709891

RESUMO

The skeletal muscle T-tubule is a specialized membrane domain essential for coordinated muscle contraction. However, in the absence of genetically tractable systems the mechanisms involved in T-tubule formation are unknown. Here, we use the optically transparent and genetically tractable zebrafish system to probe T-tubule development in vivo. By combining live imaging of transgenic markers with three-dimensional electron microscopy, we derive a four-dimensional quantitative model for T-tubule formation. To elucidate the mechanisms involved in T-tubule formation in vivo, we develop a quantitative screen for proteins that associate with and modulate early T-tubule formation, including an overexpression screen of the entire zebrafish Rab protein family. We propose an endocytic capture model involving firstly, formation of dynamic endocytic tubules at transient nucleation sites on the sarcolemma, secondly, stabilization by myofibrils/sarcoplasmic reticulum and finally, delivery of membrane from the recycling endosome and Golgi complex.


Assuntos
Contração Muscular/fisiologia , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Sarcolema/fisiologia , Sarcolema/ultraestrutura , Animais , Canais de Cálcio/metabolismo , Canais de Cálcio/ultraestrutura , Canais de Cálcio Tipo L/metabolismo , Proteínas de Transporte/metabolismo , Biologia do Desenvolvimento , Complexo de Golgi/metabolismo , Masculino , Microscopia Eletrônica , Proteínas Musculares/química , Músculo Esquelético/química , Miofibrilas/metabolismo , Sarcolema/química , Retículo Sarcoplasmático/metabolismo , Peixe-Zebra
18.
PLoS Comput Biol ; 16(7): e1008079, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32730244

RESUMO

Exercise training elicits profound metabolic adaptations in skeletal muscle cells. A key molecule in coordinating these adaptations is AMP-activated protein kinase (AMPK), whose activity increases in response to cellular energy demand. AMPK activity dynamics are primarily controlled by the adenine nucleotides ADP and AMP, but how each contributes to its control in skeletal muscle during exercise is unclear. We developed and validated a mathematical model of AMPK signaling dynamics, and then applied global parameter sensitivity analyses with data-informed constraints to predict that AMPK activity dynamics are determined principally by ADP and not AMP. We then used the model to predict the effects of two additional direct-binding activators of AMPK, ZMP and Compound 991, further validating the model and demonstrating its applicability to understanding AMPK pharmacology. The relative effects of direct-binding activators can be understood in terms of four properties, namely their concentrations, binding affinities for AMPK, abilities to enhance AMPK phosphorylation, and the magnitudes of their allosteric activation of AMPK. Despite AMP's favorable values in three of these four properties, ADP is the dominant controller of AMPK activity dynamics in skeletal muscle during exercise by virtue of its higher concentration compared to that of AMP.


Assuntos
Proteínas Quinases Ativadas por AMP , Difosfato de Adenosina , Exercício Físico/fisiologia , Músculo Esquelético , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/metabolismo , Difosfato de Adenosina/química , Difosfato de Adenosina/metabolismo , Difosfato de Adenosina/farmacocinética , Animais , Biologia Computacional , Humanos , Camundongos , Modelos Biológicos , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Transdução de Sinais/fisiologia
20.
Chem Biol Interact ; 330: 109198, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692981

RESUMO

Quercetin 3-O-beta-d-glucopyranoside (isoquercetin) is one of the most frequent metabolites of the Passiflora ligularis Juss. The purpose of this study was to investigate the effect of the aqueous extract and ethanol fraction from P. ligularis Juss leaves on glycaemia and the mechanism of action of isoquercetin on glucose uptake. In the glucose tolerance test, the aqueous extract and ethanol fraction from P. ligularis Juss (125 mg/kg to 500 mg/kg o. g.) reduced glycaemia and increased the hepatic and muscular glycogen content. Phytochemical analysis evidenced the dominant presence of isoquercetin in the extract and fraction from leaves of P. ligularis Juss. Isoquercetin mediates the stimulatory effect on glucose uptake independent of insulin receptor activation but, involve PI3K, MAPK, MEK/ERK pathways and de novo protein synthesis to GLUT-4 translocation. Overall findings revealed that isoquercetin and aqueous extract and ethanol fraction of P. ligularis Juss leaves might be a promising functional food or medicine for the treatment or prevention of diabetes.


Assuntos
Glucose/farmacocinética , Músculo Esquelético/metabolismo , Passiflora/química , Quercetina/análogos & derivados , Animais , Transporte Biológico , Diabetes Mellitus/prevenção & controle , Transportador de Glucose Tipo 4/metabolismo , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Folhas de Planta/química , Quercetina/isolamento & purificação , Quercetina/farmacologia , Ratos
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