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1.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(6): 975-980, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34841764

RESUMO

Objective: To investigate the role of cisatracurium in diaphragm atrophy in mechanically ventilated (MV) rats and its possible mechanism. Methods: 30 adult male Sprague-Dawley (SD) rats were randomly assigned to 5 groups: Rats in the control (CON) group ( n=6) were fasted for 30 h without any other intervention; rats in the MV group ( n=6) were fasted for 6 h, and then mechanically ventilated for 24 h while receiving continuous infusion of sodium pentobarbital and 0.9% NaCl; rats in the MV+cisatracurium (MVC) group ( n=6) were fasted for 6 h, and then mechanically ventilated for 24 h while receiving continuous infusion of sodium pentobarbital and cisatracurium; rats in the MV+chloroquine (QMV) group ( n=6) and rats in the MV+cisatracurium+chloroquine (QMVC) group ( n=6) received intraperitoneal injection of chloroquine (30 mg/kg), an autophagy inhibitor, at 24 h and 30 min prior to MV in addition to the treatments given to the MV group and the MVC group, respectively. The rats in each group were sacrificed 30 hours later, and costal diaphragm muscle specimens were collected. The cross-sectional area (CSA) of the diaphragm fibers was observed through HE staining, and the colocalizations of TOM20 and LC3 were assessed by immunofluorescence staining. The expression levels of PINK1, Parkin, P62 and LC3, the mitophagy-related proteins, and the expression levels of MAFbx and MURF-1, muscular-atrophy-related proteins, were evaluated by Western blot. Results: Respective comparisons of the MV group with the CON group and the MVC group with the MV group showed that the CSA decreased ( P<0.05), the expression of MURF-1, MAFbx, PINK1, Parkin and LC3Ⅱ/Ⅰproteins increased ( P<0.05), the number of co-expressed mitochondria of TOM20 and LC3 and the expression of LC3 increased and the expression of P62 protein decreased ( P<0.05) in the MV and MVC groups. Respective comparisons of the QMV group with the MV group and the QMVC group with the MVC group showed that the CSA increased ( P<0.05), the expression of MURF-1, MAFbx, PINK1, Parkin and LC3Ⅱ/Ⅰ proteins increased ( P<0.05), the number of co-expressed mitochondria of TOM20 and LC3 and the expression of LC3 decreased and the expression of P62 protein decreased ( P<0.05) in the QMV and QMVC group. Conclusion: Mechanical ventilation for 24 h caused diaphragm atrophy in SD rats. Cisatracurium may aggravate diaphragm atrophy in mechanically ventilated rats through the autophagy-lysosome (AL) pathway, a process that may be related to the PINK1/Parkin-mediated mitophagy, and chloroquine may reduce diaphragmatic atrophy induced by cisatracurium by blocking the AL pathway.


Assuntos
Diafragma , Respiração Artificial , Animais , Atracúrio/análogos & derivados , Diafragma/patologia , Masculino , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Ratos , Ratos Sprague-Dawley , Respiração Artificial/efeitos adversos
2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(5): 566-570, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34816675

RESUMO

Objective: To investigate the effects of Atrolnc-1 on immobilization induced muscular atrophy in mice hindlimbs. Methods: Male C57BL/6 mice were randomly divided into control group and immobilization group (n=10 per group). The control group did not receive any treatment. The right hindlimb of the Iimmobilization group was fixed by self-made plastic tube. After 2 weeks' immobilization, the gastrocnemius muscle was separated. Hematoxylin-eosin (HE) staining was used to observe the morphological changes and the cross-sectional area was calculated. The expressions of Atrogin-1 and atrophy-specific long non-coding RNA Atrolnc-1 were detected by quantitative real-time PCR (QRT-PCR). Western blot (WB) was used to detect the expressions of muscular atrophy fbox-1 protein (MAFbx/Atrogin-1), muscle ring finger1 (MuRF-1) in whole cell and phosphonated of nuclear factor kappaB (p-NF-κB) in cytoplasm and nucleus. Results: The gastrocnemius muscle was atrophy after 2 weeks' immobilization. Compared with the control group, the wet weight of gastrocnemius muscle was decreased (P>0.05) and the permillage of wet weight/weight of gastrocnemius muscle was decreased significantly (P<0.05). HE staining showed that the number of muscle fibers in the immobilization group were reduced, the muscle fibers were dissolved and arranged disorderly and the interstitial inflammatory cells were infiltrated; the cross-sectional area of muscle fibers was decreased (P<0.01).The expression level of atrolnc-1 was increased in immobilization group (P<0.01). The expression level of p-NF-κB in cytoplasm was decreased (P<0.01), while the expression level of p-NF-κB was increased in nucleus ( P<0.01). Besides, the expressions of atrogin-1 (P<0.01) and MuRF-1 (P<0.01) were increased. Conclusion: Immobilization induced gastrocnemius atrophy in mice may be related to the activation of NF-κB by Atrolnc-1 and then promote MuRF-1 expression.


Assuntos
Músculo Esquelético , Atrofia Muscular , Animais , Membro Posterior , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas , Músculo Esquelético/patologia
3.
J Nutr Sci Vitaminol (Tokyo) ; 67(5): 351-357, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34719621

RESUMO

Atrogin-1, which is an important regulator of ubiquitin-mediated protein degradation in skeletal muscle, is a major marker of muscle loss and disuse muscle atrophy. To investigate which components of lactic acid bacteria (LAB) suppress dexamethasone (DEX)-induced atrogin-1 expression, mouse skeletal muscle C2C12 myotubes were treated with DEX in the presence or absence of components of LAB. Heat-killed cells and lipoteichoic acid (LTA) derived from five LAB strains significantly suppressed DEX-induced atrogin-1 expression. The glycerophosphate (GroP) fraction prepared from chemically-degraded LTA and sn-glycerol-1-phosphate suppressed DEX-induced atrogin-1 expression, whereas the glycolipid anchor fraction of LTA did not. Heat-killed cells obtained by culturing under low-Mn2+ conditions, which generated fewer poly-GroP polymers in LTA, displayed significantly lower inhibitory activity compared to heat-killed cells grown under normal conditions. These results suggested that LTA of LAB contributed to suppressing atrogin-1 expression and that the GroP moiety of LTA was responsible for its inhibitory activity.


Assuntos
Lactobacillales , Atrofia Muscular , Animais , Dexametasona/farmacologia , Glicerofosfatos , Lipopolissacarídeos , Camundongos , Fibras Musculares Esqueléticas , Proteínas Musculares , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Proteínas Ligases SKP Culina F-Box , Ácidos Teicoicos , Ubiquitina-Proteína Ligases
4.
Int J Mol Sci ; 22(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769017

RESUMO

Muscle fatigue (MF) declines the capacity of muscles to complete a task over time at a constant load. MF is usually short-lasting, reversible, and is experienced as a feeling of tiredness or lack of energy. The leading causes of short-lasting fatigue are related to overtraining, undertraining/deconditioning, or physical injury. Conversely, MF can be persistent and more serious when associated with pathological states or following chronic exposure to certain medication or toxic composites. In conjunction with chronic fatigue, the muscle feels floppy, and the force generated by muscles is always low, causing the individual to feel frail constantly. The leading cause underpinning the development of chronic fatigue is related to muscle wasting mediated by aging, immobilization, insulin resistance (through high-fat dietary intake or pharmacologically mediated Peroxisome Proliferator-Activated Receptor (PPAR) agonism), diseases associated with systemic inflammation (arthritis, sepsis, infections, trauma, cardiovascular and respiratory disorders (heart failure, chronic obstructive pulmonary disease (COPD))), chronic kidney failure, muscle dystrophies, muscle myopathies, multiple sclerosis, and, more recently, coronavirus disease 2019 (COVID-19). The primary outcome of displaying chronic muscle fatigue is a poor quality of life. This type of fatigue represents a significant daily challenge for those affected and for the national health authorities through the financial burden attached to patient support. Although the origin of chronic fatigue is multifactorial, the MF in illness conditions is intrinsically linked to the occurrence of muscle loss. The sequence of events leading to chronic fatigue can be schematically denoted as: trigger (genetic or pathological) -> molecular outcome within the muscle cell -> muscle wasting -> loss of muscle function -> occurrence of chronic muscle fatigue. The present review will only highlight and discuss current knowledge on the molecular mechanisms that contribute to the upregulation of muscle wasting, thereby helping us understand how we could prevent or treat this debilitating condition.


Assuntos
Fadiga Muscular/fisiologia , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiologia , Autofagia , COVID-19/fisiopatologia , Estado Terminal , Humanos , Resistência à Insulina , Lisossomos/metabolismo , Fadiga Muscular/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Atrofia Muscular/etiologia , Sarcopenia/fisiopatologia
5.
J Muscle Res Cell Motil ; 42(3-4): 429-441, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34687403

RESUMO

To investigate the effects of treadmill running on two different types of skeletal muscle, we established a rat model of collagen-induced arthritis (CIA). The skeletal muscles studied were the extensor digitorum longus (EDL), which is rich in fast-twitch muscle fibers, and the soleus, which is rich in slow-twitch muscle fibers. The histological and transcriptional changes in these muscles at 14 and 44 days after immunosensitization were compared between rats that were forced to exercise (CIA ex group) and free-reared CIA rats (CIA no group). Change in protein expression was examined on day 14 after a single bout of treadmill running. Treadmill running had different effects on the relative muscle weight and total and fiber cross-sectional areas in each muscle type. In the soleus, it prevented muscle atrophy. Transcriptional analysis revealed increased eukaryotic translation initiation factor 4E (Eif4e) expression on day 14 and increased Atrogin-1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression on day 44 in the soleus in the CIA ex group, suggesting an interaction between muscle type and exercise. A single bout of treadmill running increased the level of Eif4e and p70S6K and decreased that of Atrogin-1 in the soleus on day 14. Treadmill running prevented muscle atrophy in the soleus in a rat model of rheumatoid arthritis via activation of mitochondrial function, as evidenced by increased PGC-1α expression.


Assuntos
Artrite Reumatoide , Corrida , Animais , Artrite Reumatoide/patologia , Fator de Iniciação 4E em Eucariotos , Fibras Musculares de Contração Rápida , Fibras Musculares de Contração Lenta , Músculo Esquelético , Atrofia Muscular/patologia , Atrofia Muscular/prevenção & controle , Condicionamento Físico Animal , Ratos
6.
Clin Nutr ESPEN ; 45: 503-506, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34620362

RESUMO

BACKGROUND & AIMS: Muscle atrophy is a public health issue and inflammation is a major cause of muscle atrophy. While docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are typical ω-3 polyunsaturated fatty acids, are reported to have anti-inflammatory effects on endotoxin-induced inflammatory responses, their effects on inflammatory muscle atrophy have not been clarified. In this study, we aimed to investigate the effects of DHA and EPA on inflammatory muscle atrophy. METHODS: DHA or EPA was added to C2C12 myotubes at a concentration of 25, 50, or 100 µM, and 1 h later, lipopolysaccharide (LPS) was added at a concentration of 1 µg/mL. Two hours after the first LPS addition, mRNA expression of atrogin-1 and Murf-1 in C2C12 myotubes was measured. The second LPS addition was performed 24 h after the first LPS addition, and myotube diameter, myofibrillar protein, and cell viability were measured. One-way ANOVA and Tukey's multiple comparison test were used for statistical processing of the results, and the significance level was set to less than 5 %. RESULTS: The LPS-added group significantly decreased the myotube diameter and the myofibrillar protein content compared to the control group. The myotube diameter was significantly higher in the 25 µM, 50 µM DHA and 25 µM EPA-added groups compared to the LPS group. In the 25 µM DHA and EPA-added groups, the myofibrillar protein content was significantly higher than that in the LPS group. The mRNA expression levels of atrogin-1 and murf-1 were significantly suppressed in the 25 µM DHA and EPA-added groups compared to the LPS group. The cell viability did not change by the addition of LPS, DHA, and EPA. CONCLUSIONS: The addition of DHA or EPA suppressed the decrease in myotube diameter and myofibrillar protein content and suppressed the increase in atrogin-1 and murf-1 induced by LPS. This study showed the preventive effect of DHA and EPA on endotoxin-induced muscle atrophy.


Assuntos
Ácido Eicosapentaenoico , Ácidos Graxos Ômega-3 , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Endotoxinas , Humanos , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controle
7.
BMC Musculoskelet Disord ; 22(1): 854, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625068

RESUMO

BACKGROUND: The high signal of paravertebral muscle (PVM) on T2-weighted image (T2WI) is usually considered to be fatty degeneration. However, it is difficult to distinguish inflammatory edema from fatty degeneration on T2WI. The purpose of this study was to identify different types of PVM high signal in patients with low back pain (LBP) through magnetic resonance imaging (MRI) and histology. METHODS: Seventy patients with LBP underwent MRI. The signal change of multifidus both on T2WI and fat suppression image (FSI) was quantified by Image J. Furthermore, 25 of the 70 patients underwent surgery for degenerative lumbar disease and their multifidus were obtained during the operation. Histological analysis of the samples was performed by HE staining. RESULT: Three types of PVM signal changes were identified from the MRI. Type 1 (n = 36) indicated fatty degeneration characterized by a high signal on T2WI and low signal on FSI. High signal on both T2WI and FSI, signifying type 2 meant inflammatory edema (n = 9). Type 3 (n = 25) showed high signal on T2WI and partial signal suppression on FSI, which meant a combination of fatty degeneration and inflammatory edema. Histological results were consistent with MRI. Among the 25 patients who underwent surgery, type 1 (n = 14) showed adipocytes infiltration, type 2 (n = 3) showed inflammatory cells infiltration and type 3 (n = 8) showed adipocytes and inflammatory cells infiltration. CONCLUSION: From our results, there are three types of pathological changes in patients with PVM degeneration, which may help to decide on targeted treatments for LBP.


Assuntos
Dor Lombar , Atrofia Muscular , Estudos Transversais , Humanos , Dor Lombar/diagnóstico por imagem , Dor Lombar/patologia , Imageamento por Ressonância Magnética , Atrofia Muscular/patologia , Músculos Paraespinais/patologia
8.
Arthroscopy ; 37(10): 3049-3052, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34602147

RESUMO

Rotator cuff repair is performed to effect healing of the enthesis; to restore shoulder comfort, strength, and function; to prevent tear propagation; and to prevent progression of atrophic muscle changes (fatty degeneration, fatty infiltration, and fatty atrophy) that eventually occur. Non-retracted and moderately retracted rotator cuff tears usually heal after repair, and muscle atrophy may recover over time. It follows that early rotator cuff repair is beneficial for many patients with chronic but reparable rotator cuff tears. Diagnostic ultrasound can provide quantitative information about the recovery of both muscle and tendon and represents a viable alternative to magnetic resonance imaging for evaluating healing after rotator cuff repair.


Assuntos
Lesões do Manguito Rotador , Manguito Rotador , Humanos , Atrofia Muscular/diagnóstico por imagem , Manguito Rotador/diagnóstico por imagem , Manguito Rotador/patologia , Manguito Rotador/cirurgia , Lesões do Manguito Rotador/diagnóstico por imagem , Lesões do Manguito Rotador/patologia , Lesões do Manguito Rotador/cirurgia , Tendões , Ultrassonografia
9.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638792

RESUMO

Skeletal muscle unloading results in atrophy. We hypothesized that pannexin 1 ATP-permeable channel (PANX1) is involved in the response of muscle to unloading. We tested this hypothesis by blocking PANX1, which regulates efflux of ATP from the cytoplasm. Rats were divided into six groups (eight rats each): non-treated control for 1 and 3 days of the experiments (1C and 3C, respectively), 1 and 3 days of hindlimb suspension (HS) with placebo (1H and 3H, respectively), and 1 and 3 days of HS with PANX1 inhibitor probenecid (PRB; 1HP and 3HP, respectively). When compared with 3C group there was a significant increase in ATP in soleus muscle of 3H and 3HP groups (32 and 51%, respectively, p < 0.05). When compared with 3H group, 3HP group had: (1) lower mRNA expression of E3 ligases MuRF1 and MAFbx (by 50 and 38% respectively, p < 0.05) and MYOG (by 34%, p < 0.05); (2) higher phosphorylation of p70S6k and p90RSK (by 51 and 35% respectively, p < 0.05); (3) lower levels of phosphorylated eEF2 (by 157%, p < 0.05); (4) higher level of phosphorylated GSK3ß (by 189%, p < 0.05). In conclusion, PANX1 ATP-permeable channels are involved in the regulation of muscle atrophic processes by modulating expression of E3 ligases, and protein translation and elongation processes during unloading.


Assuntos
Conexinas/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais , Animais , Elevação dos Membros Posteriores , Masculino , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Ratos , Ratos Wistar
10.
Chin J Physiol ; 64(5): 211-217, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34708712

RESUMO

This study aimed to investigate the effect of mealworm (Tenebrio molitor) derived protein supplementation on skeletal muscle atrophy of hindlimb casted immobilized rats. Twenty-four six-week-old male Sprague-Dawley rats were randomly divided into three groups: control sedentary group (CD, n = 8), control diet casting group (CDC, n = 8), and the mealworm-derived protein supplemented casting group (MDC, n = 8). CD and CDC group was supplemented AIN-76G diet and mealworm-derived protein supplemented diet for MDC group was substituted as 5% casein protein to 5% mealworm protein for 5 weeks and left hindlimb casting immobilization using casting tape for CDC and MDC group was done 1 week before sacrifice. After 5 weeks of mealworm supplementation, the soleus muscle weight of the MDC group was significantly higher compared to the CDC group. In addition, the level of muscle protein synthesis factors p-Akt/Akt, p-4EBP1/4EBP1, and p-S6K/S6K significantly increased in the MDC group compared to the CDC group. On contrary, the level of muscle protein degradation factors (MuRF1 and atrogin-1) was significantly lower in the MDC group than that of the CDC group. These results suggest that mealworm-derived protein supplementation may have a significant role in the prevention of skeletal muscle atrophy via stimulation of muscle protein synthesis factors and inhibition of muscle protein degradation factors, and therefore a promising intervention in sarcopenia.


Assuntos
Tenebrio , Animais , Suplementos Nutricionais , Membro Posterior/patologia , Masculino , Músculo Esquelético , Atrofia Muscular/patologia , Atrofia Muscular/prevenção & controle , Ratos , Ratos Sprague-Dawley
12.
Cells ; 10(9)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34572085

RESUMO

We hypothesized that the phenolic compound resveratrol mitigates muscle protein degradation and loss and improves muscle fiber cross-sectional area (CSA) in gastrocnemius of mice exposed to unloading (7dI). In gastrocnemius of mice (female C57BL/6J, 10 weeks) exposed to a seven-day period of hindlimb immobilization with/without resveratrol treatment, markers of muscle proteolysis (tyrosine release, systemic troponin-I), atrophy signaling pathways, and muscle phenotypic features and function were analyzed. In gastrocnemius of unloaded mice treated with resveratrol, body and muscle weight and function were attenuated, whereas muscle proteolysis (tyrosine release), proteolytic and apoptotic markers, atrophy signaling pathways, and myofiber CSA significantly improved. Resveratrol treatment of mice exposed to a seven-day period of unloading prevented body and muscle weight and limb strength loss, while an improvement in muscle proteolysis, proteolytic markers, atrophy signaling pathways, apoptosis, and muscle fiber CSA was observed in the gastrocnemius muscle. These findings may have potential therapeutic implications in the management of disuse muscle atrophy in clinical settings.


Assuntos
Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Resveratrol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Feminino , Elevação dos Membros Posteriores , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/patologia , Fenótipo , Transdução de Sinais/efeitos dos fármacos
13.
Dev Cell ; 56(18): 2664-2680.e6, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34473940

RESUMO

Cachexia, the wasting syndrome commonly observed in advanced cancer patients, accounts for up to one-third of cancer-related mortalities. We have established a Drosophila larval model of organ wasting whereby epithelial overgrowth in eye-antennal discs leads to wasting of the adipose tissue and muscles. The wasting is associated with fat-body remodeling and muscle detachment and is dependent on tumor-secreted matrix metalloproteinase 1 (Mmp1). Mmp1 can both modulate TGFß signaling in the fat body and disrupt basement membrane (BM)/extracellular matrix (ECM) protein localization in both the fat body and the muscle. Inhibition of TGFß signaling or Mmps in the fat body/muscle using a QF2-QUAS binary expression system rescues muscle wasting in the presence of tumor. Altogether, our study proposes that tumor-derived Mmps are central mediators of organ wasting in cancer cachexia.


Assuntos
Tecido Adiposo/metabolismo , Metaloproteinases da Matriz/metabolismo , Músculo Esquelético/metabolismo , Neoplasias/metabolismo , Animais , Membrana Basal/metabolismo , Drosophila/metabolismo , Matriz Extracelular/metabolismo , Atrofia Muscular/metabolismo
14.
Nutrients ; 13(9)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34579038

RESUMO

An excessive fat diet induces intramuscular fat deposition that accumulates as a form of lipid droplet (LD) and leads to lipotoxicity, including muscle atrophy or decreasing muscle strength. Lipotoxicity depends on the number of LDs, subcellular distribution (intermyofibrillar, IMF, LDs or subsarcolemmal, SS), and fiber type-specific differences (type I or type II fiber) as well as the size of LD. Ecklonia cava extracts (ECE), which is known to increase peroxisome proliferator-activated receptor alpha (PPAR-α), which leads to decreasing expression level of perilipin2 (PLIN2). PLIN2 is involved in modulating the size of LDs. This study shows that ECE and dieckol could decrease PLIN2 expression and decrease the size and number of LDs in the muscle of high-fat diet (HF)-fed animals and lead to attenuating muscle atrophy. Expression level of PPAR-α was decreased, and PLIN2 was increased by HF. ECE and dieckol increased PPAR-α expression and decreased PLIN2. The diameter of LDs was increased in high-fat diet condition, and it was decreased by ECE or dieckol treatment. The number of LDs in type II fibers/total LDs was increased by HF and it was decreased by ECE or dieckol. The SS LDs were increased, and IMF LDs were decreased by HF. ECE or dieckol decreased SS LDs and increased IMF LDs. The ECE or dieckol attenuated the upregulation of muscle atrophy-related genes including Murf1, Atrogin-1, and p53 by HF. ECE or dieckol increased the cross-sectional area of the muscle fibers and grip strength, which were decreased by HF. In conclusion, ECE or dieckol decreased the size of LDs and modulated the contribution of LDs to less toxic ones by decreasing PLIN2 expression and thus attenuated muscle atrophy and strength, which were induced by HF.


Assuntos
Benzofuranos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Gotículas Lipídicas/metabolismo , Músculo Esquelético/fisiologia , Atrofia Muscular/induzido quimicamente , Animais , Gorduras na Dieta , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Força Muscular , PPAR alfa , Perilipina-1/genética , Perilipina-1/metabolismo , Feófitas/química
15.
Front Immunol ; 12: 689966, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34566957

RESUMO

Background: Most of the explanatory and prognostic models of COVID-19 lack of a comprehensive assessment of the wide COVID-19 spectrum of abnormalities. The aim of this study was to unveil novel biological features to explain COVID-19 severity and prognosis (death and disease progression). Methods: A predictive model for COVID-19 severity in 121 patients was constructed by ordinal logistic regression calculating odds ratio (OR) with 95% confidence intervals (95% CI) for a set of clinical, immunological, metabolomic, and other biological traits. The accuracy and calibration of the model was tested with the area under the curve (AUC), Somer's D, and calibration plot. Hazard ratios with 95% CI for adverse outcomes were calculated with a Cox proportional-hazards model. Results: The explanatory variables for COVID-19 severity were the body mass index (BMI), hemoglobin, albumin, 3-Hydroxyisovaleric acid, CD8+ effector memory T cells, Th1 cells, low-density granulocytes, monocyte chemoattractant protein-1, plasma TRIM63, and circulating neutrophil extracellular traps. The model showed an outstanding performance with an optimism-adjusted AUC of 0.999, and Somer's D of 0.999. The predictive variables for adverse outcomes in COVID-19 were severe and critical disease diagnosis, BMI, lactate dehydrogenase, Troponin I, neutrophil/lymphocyte ratio, serum levels of IP-10, malic acid, 3, 4 di-hydroxybutanoic acid, citric acid, myoinositol, and cystine. Conclusions: Herein, we unveil novel immunological and metabolomic features associated with COVID-19 severity and prognosis. Our models encompass the interplay among innate and adaptive immunity, inflammation-induced muscle atrophy and hypoxia as the main drivers of COVID-19 severity.


Assuntos
COVID-19 , SARS-CoV-2 , Índice de Gravidade de Doença , Adulto , Coagulação Sanguínea , Índice de Massa Corporal , COVID-19/sangue , COVID-19/imunologia , COVID-19/metabolismo , Citocinas/sangue , Armadilhas Extracelulares/imunologia , Feminino , Hemoglobinas/análise , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Atrofia Muscular , Neutrófilos/imunologia , Fenótipo , Prognóstico , Albumina Sérica Humana/análise , Linfócitos T/imunologia , Valeratos/sangue
16.
Cells ; 10(9)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34571935

RESUMO

Type 1 diabetes mellitus is an autoimmune disease caused by the destruction of pancreatic beta cells. Many patients with type 1 diabetes experience skeletal muscle wasting. Although the link between type 1 diabetes and muscle wasting is not clearly known, insulin insufficiency and hyperglycemia may contribute to decreased muscle mass. In this study, we investigated the therapeutic effect of the ethanolic extract of Schisandrae chinensis Fructus (SFe) on muscle wasting in streptozotocin (STZ)-induced diabetic mice. STZ-diabetic C57BL/6 mice (blood glucose level ≥300 mg/dL) were orally administered SFe (250 or 500 mg/kg/day) for 6 weeks. We observed that SFe administration did not change blood glucose levels but increased gastrocnemius muscle weight, cross-sectional area, and grip strength in STZ-induced diabetic mice. Administration of SFe (500 mg/kg) decreased the expression of atrophic factors, such as MuRF1 and atrogin-1, but did not alter the expression of muscle synthetic factors. Further studies showed that SFe administration decreased the expression of KLF15 and p-CREB, which are upstream molecules of atrophic factors. Examination of the expression of molecules involved in autophagy-lysosomal pathways (e.g., p62/SQSTM1, Atg7, Beclin-1, ULK-1, LC3-I, and LC3-II) revealed that SFe administration significantly decreased the expression of p62/SQSTM1, LC3-I, and LC3-II; however, no changes were observed in the expression of Atg7, Beclin-1, or ULK-1. Our results suggest that SFe ameliorated muscle wasting in STZ-induced diabetic mice by decreasing protein degradation via downregulation of the CREB-KLF15-mediated UPS system and the p62/SQSTM1-mediated autophagy-lysosomal pathway.


Assuntos
Autofagia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Diabetes Mellitus Experimental/complicações , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Lisossomos/metabolismo , Atrofia Muscular/tratamento farmacológico , Extratos Vegetais/farmacologia , Schisandra/química , Animais , Frutas/química , Lisossomos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia
17.
Ageing Res Rev ; 71: 101463, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34534682

RESUMO

Maintenance of skeletal muscle mass and function is an incredibly nuanced balance of anabolism and catabolism that can become distorted within different pathological conditions. In this paper we intend to discuss the distinct intracellular signaling events that regulate muscle protein atrophy for a given clinical occurrence. Aside from the common outcome of muscle deterioration, several conditions have at least one or more distinct mechanisms that creates unique intracellular environments that facilitate muscle loss. The subtle individuality to each of these given pathologies can provide both researchers and clinicians with specific targets of interest to further identify and increase the efficacy of medical treatments and interventions.


Assuntos
Caquexia , Atrofia Muscular , Caquexia/patologia , Humanos , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia , Transdução de Sinais
18.
Nutrients ; 13(9)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34578826

RESUMO

Maslinic acid (MA) is a pentacyclic triterpene abundant in olive peels. MA reportedly increases skeletal muscle mass and strength in older adults; however, the underlying mechanism is unknown. This study aimed to investigate the effects of MA on denervated muscle atrophy and strength and to explore the underlying molecular mechanism. Mice were fed either a control diet or a 0.27% MA diet. One week after intervention, the sciatic nerves of both legs were cut to induce muscle atrophy. Mice were examined 14 days after denervation. MA prevented the denervation-induced reduction in gastrocnemius muscle mass and skeletal muscle strength. Microarray gene expression profiling in gastrocnemius muscle demonstrated several potential mechanisms for muscle maintenance. Gene set enrichment analysis (GSEA) revealed different enriched biological processes, such as myogenesis, PI3/AKT/mTOR signaling, TNFα signaling via NF-κB, and TGF-ß signaling in MA-treated mice. In addition, qPCR data showed that MA induced Igf1 expression and suppressed the expressions of Atrogin-1, Murf1 and Tgfb. Altogether, our results suggest the potential of MA as a new therapeutic and preventive dietary ingredient for muscular atrophy and strength.


Assuntos
Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Triterpenos/farmacologia , Animais , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Denervação Muscular/métodos , Desenvolvimento Muscular/genética , Músculo Esquelético/inervação , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Doenças Musculares/patologia , NF-kappa B/metabolismo , Olea/química , Nervo Isquiático/lesões , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
J Physiol ; 599(20): 4581-4596, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34487346

RESUMO

Limb disuse has profound negative consequences on both vascular and skeletal muscle health. The purpose of this investigation was to determine whether repeated application of passive heat, applied to the knee extensor muscles, could mitigate the detrimental effects of limb disuse on vascular function. This was a randomized, single-blinded placebo controlled trial. Twenty-one healthy volunteers (10 women, 11 men) underwent 10 days of unilateral lower limb immobilization and were randomized to receive either a daily 2 h sham (Imm) or heat treatment (Imm+H) using pulsed shortwave diathermy. Vascular function was assessed with Doppler ultrasound of the femoral artery and the passive leg movement technique. Biopsies of the vastus lateralis were also collected before and after the intervention. In Imm, femoral artery diameter (FAD) and PLM-induced hyperaemia (HYP) were reduced by 7.3% and 34.3%, respectively. Changes in both FAD (4% decrease; P = 0.0006) and HYP (7.8% increase; P = 0.003) were significantly attenuated in Imm+H. Vastus lateralis capillary density was not altered in either group. Immobilization significantly decreased expression of vascular endothelial growth factor (P = 0.006) and Akt (P = 0.001), and increased expression of angiopoietin 2 (P = 0.0004) over time, with no differences found between groups. Immobilization also upregulated elements associated with remodelling of the extracellular matrix, including matrix metalloproteinase 2 (P = 0.0046) and fibronectin (P = 0.0163), with no differences found between groups. In conclusion, limb immobilization impairs vascular endothelial function, but daily muscle heating via diathermy is sufficient to counteract this adverse effect. These are the first data to indicate that passive muscle heating mitigates disuse-induced vascular dysfunction. KEY POINTS: Limb disuse can be unavoidable for many of reasons (i.e. injury, bed rest, post-surgery), and can have significant adverse consequences for muscular and vascular health. We tested the hypothesis that declines in vascular function that result from lower limb immobilization could be mitigated by application of passive heat therapy. This report shows that 10 days of limb immobilization significantly decreases resistance artery diameter and vascular function, and that application of passive heat to the knee extensor muscle group each day for 2 h per day is sufficient to attenuate these declines. Additionally, muscle biopsy analyses showed that 10 days of heat therapy does not alter capillary density of the muscle, but upregulates multiple factors indicative of a vascular remodelling response. Our data demonstrate the utility of passive heat as a therapeutic tool to mitigate losses in lower limb vascular function that occur from disuse.


Assuntos
Calefação , Metaloproteinase 2 da Matriz , Feminino , Humanos , Imobilização , Masculino , Força Muscular , Músculo Esquelético , Atrofia Muscular/patologia , Músculo Quadríceps/diagnóstico por imagem , Músculo Quadríceps/patologia , Fator A de Crescimento do Endotélio Vascular
20.
FASEB J ; 35(10): e21914, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34547132

RESUMO

Limb-girdle muscular dystrophy D2 (LGMDD2) is an ultrarare autosomal dominant myopathy caused by mutation of the normal stop codon of the TNPO3 nuclear importin. The mutant protein carries a 15 amino acid C-terminal extension associated with pathogenicity. Here we report the first animal model of the disease by expressing the human mutant TNPO3 gene in Drosophila musculature or motor neurons and concomitantly silencing the endogenous expression of the fly protein ortholog. A similar genotype expressing wildtype TNPO3 served as a control. Phenotypes characterization revealed that mutant TNPO3 expression targeted at muscles or motor neurons caused LGMDD2-like phenotypes such as muscle degeneration and atrophy, and reduced locomotor ability. Notably, LGMDD2 mutation increase TNPO3 at the transcript and protein level in the Drosophila model Upregulated muscle autophagy observed in LGMDD2 patients was also confirmed in the fly model, in which the anti-autophagic drug chloroquine was able to rescue histologic and functional phenotypes. Overall, we provide a proof of concept of autophagy as a target to treat disease phenotypes and propose a neurogenic component to explain mutant TNPO3 pathogenicity in diseased muscles.


Assuntos
Autofagia/efeitos dos fármacos , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Modelos Animais de Doenças , Drosophila melanogaster/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/complicações , Animais , Animais Geneticamente Modificados , Autofagia/genética , Drosophila melanogaster/genética , Feminino , Humanos , Hormônios de Inseto , Locomoção , Masculino , Neurônios Motores/metabolismo , Músculos/metabolismo , Atrofia Muscular/complicações , Atrofia Muscular/genética , Atrofia Muscular/patologia , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Fenótipo , Taxa de Sobrevida , beta Carioferinas/genética , beta Carioferinas/metabolismo
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