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1.
Science ; 373(6551): 223-225, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244415

RESUMO

Basal metabolic rate generally scales with body mass in mammals, and variation from predicted levels indicates adaptive metabolic remodeling. As a thermogenic adaptation for living in cool water, sea otters have a basal metabolic rate approximately three times that of the predicted rate; however, the tissue-level source of this hypermetabolism is unknown. Because skeletal muscle is a major determinant of whole-body metabolism, we characterized respiratory capacity and thermogenic leak in sea otter muscle. Compared with that of previously sampled mammals, thermogenic muscle leak capacity was elevated and could account for sea otter hypermetabolism. Muscle respiratory capacity was modestly elevated and reached adult levels in neonates. Premature metabolic development and high leak rate indicate that sea otter muscle metabolism is regulated by thermogenic demand and is the source of basal hypermetabolism.


Assuntos
Músculo Esquelético/fisiologia , Lontras/fisiologia , Termogênese , Envelhecimento , Animais , Animais Recém-Nascidos/fisiologia , Metabolismo Basal , Tamanho Corporal , Temperatura Baixa , Músculo Esquelético/metabolismo , Lontras/metabolismo , Consumo de Oxigênio
2.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281273

RESUMO

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/etiologia , Hipóxia/metabolismo , Distrofias Musculares/complicações , Distrofias Musculares/metabolismo , Animais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Isquemia/etiologia , Modelos Biológicos , Desenvolvimento Muscular , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Distrofias Musculares/genética , Estresse Oxidativo , Regeneração , Transdução de Sinais
3.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281282

RESUMO

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 µM) for 24 and 72 h. Acrolein (0.5-2 µM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/ß. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.


Assuntos
Acroleína/toxicidade , Transportador de Glucose Tipo 4/antagonistas & inibidores , Glucose/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Acroleína/administração & dosagem , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Glicemia/metabolismo , Linhagem Celular , Intolerância à Glucose/induzido quimicamente , Intolerância à Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201319

RESUMO

Proper skeletal muscle function is controlled by intracellular Ca2+ concentration and by efficient production of energy (ATP), which, in turn, depend on: (a) the release and re-uptake of Ca2+ from sarcoplasmic-reticulum (SR) during excitation-contraction (EC) coupling, which controls the contraction and relaxation of sarcomeres; (b) the uptake of Ca2+ into the mitochondrial matrix, which stimulates aerobic ATP production; and finally (c) the entry of Ca2+ from the extracellular space via store-operated Ca2+ entry (SOCE), a mechanism that is important to limit/delay muscle fatigue. Abnormalities in Ca2+ handling underlie many physio-pathological conditions, including dysfunction in ageing. The specific focus of this review is to discuss the importance of the proper architecture of organelles and membrane systems involved in the mechanisms introduced above for the correct skeletal muscle function. We reviewed the existing literature about EC coupling, mitochondrial Ca2+ uptake, SOCE and about the structural membranes and organelles deputed to those functions and finally, we summarized the data collected in different, but complementary, projects studying changes caused by denervation and ageing to the structure and positioning of those organelles: a. denervation of muscle fibers-an event that contributes, to some degree, to muscle loss in ageing (known as sarcopenia)-causes misplacement and damage: (i) of membrane structures involved in EC coupling (calcium release units, CRUs) and (ii) of the mitochondrial network; b. sedentary ageing causes partial disarray/damage of CRUs and of calcium entry units (CEUs, structures involved in SOCE) and loss/misplacement of mitochondria; c. functional electrical stimulation (FES) and regular exercise promote the rescue/maintenance of the proper architecture of CRUs, CEUs, and of mitochondria in both denervation and ageing. All these structural changes were accompanied by related functional changes, i.e., loss/decay in function caused by denervation and ageing, and improved function following FES or exercise. These data suggest that the integrity and proper disposition of intracellular organelles deputed to Ca2+ handling and aerobic generation of ATP is challenged by inactivity (or reduced activity); modifications in the architecture of these intracellular membrane systems may contribute to muscle dysfunction in ageing and sarcopenia.


Assuntos
Trifosfato de Adenosina/metabolismo , Envelhecimento/patologia , Cálcio/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/patologia , Organelas/patologia , Envelhecimento/metabolismo , Animais , Humanos , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Organelas/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-34199730

RESUMO

Padel is becoming one of the most widespread racket sports that may have potential health benefits. Considering that several myokines mediate the cross-talk between skeletal muscles and the brain, exerting positive effects on brain health status, this study was designed to evaluate the responses of brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), and irisin (IR) to padel competition in trained players and to determine whether these responses were sex-dependent. Twenty-four trained padel players (14 women and 10 men with a mean age of 27.8 ± 6.3 years) participated voluntarily in this study. Circulating levels of BDNF, LIF, and IR were assessed before and after simulated padel competition (real playing time, 27.8 ± 8.49 min; relative intensity, 75.2 ± 7.9% maximum heart rate). Except for BDNF responses observed in female players (increasing from 1531.12 ± 269.09 to 1768.56 ± 410.75 ng/mL), no significant changes in LIF and IR concentrations were reported after padel competition. In addition, no sex-related differences were found. Moreover, significant associations between IR and BDNF were established at both pre- and post-competition. Our results suggest that while competitive padel practice stimulates BDNF response in female players, padel competition failed to boost the release of LIF and IR. Future studies are needed to further explore the role of these exercise-induced myokines in the regulation of brain functions and to identify the field sports that can contribute to myokine-mediated muscle-brain crosstalk.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Encéfalo , Adulto , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Nível de Saúde , Humanos , Masculino , Músculo Esquelético/metabolismo , Caracteres Sexuais , Fatores de Transcrição , Adulto Jovem
6.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206382

RESUMO

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD). Evidence is accumulating that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has not been fully elucidated. Here, we show that emerin downregulates Signal transducer and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus kinase (JAK). Deletion mutation experiments show that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacts directly and co-localizes with STAT3 in the nuclear membrane. Emerin knockdown induces STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin, by assembling with BAF and lamin A/C, acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induces STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and may be a new therapeutic target for treatment.


Assuntos
Proteínas de Membrana/metabolismo , Membrana Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células A549 , Núcleo Celular/metabolismo , Sobrevivência Celular , Regulação da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Músculo Esquelético/metabolismo , Distrofias Musculares/etiologia , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Mutação , Ligação Proteica , Fator de Transcrição STAT3/genética , Fatores de Transcrição/metabolismo
7.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209117

RESUMO

Progressive loss of muscle and muscle function is associated with significant fibrosis in Duchenne muscular dystrophy (DMD) patients. Halofuginone, an analog of febrifugine, prevents fibrosis in various animal models, including those of muscular dystrophies. Effects of (+)/(-)-halofuginone enantiomers on motor coordination and diaphragm histopathology in mdx mice, the mouse model for DMD, were examined. Four-week-old male mice were treated with racemic halofuginone, or its separate enantiomers, for 10 weeks. Controls were treated with saline. Racemic halofuginone-treated mice demonstrated better motor coordination and balance than controls. However, (+)-halofuginone surpassed the racemic form's effect. No effect was observed for (-)-halofuginone, which behaved like the control. A significant reduction in collagen content and degenerative areas, and an increase in utrophin levels were observed in diaphragms of mice treated with racemic halofuginone. Again, (+)-halofuginone was more effective than the racemic form, whereas (-)-halofuginone had no effect. Both racemic and (+)-halofuginone increased diaphragm myofiber diameters, with no effect for (-)-halofuginone. No effects were observed for any of the compounds tested in an in-vitro cell viability assay. These results, demonstrating a differential effect of the halofuginone enantiomers and superiority of (+)-halofuginone, are of great importance for future use of (+)-halofuginone as a DMD antifibrotic therapy.


Assuntos
Músculo Esquelético , Distrofia Muscular de Duchenne , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Animais , Modelos Animais de Doenças , Fibrose , Masculino , Camundongos , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia
8.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204228

RESUMO

Regular exercise is associated with pronounced health benefits. The molecular processes involved in physiological adaptations to exercise are best understood in skeletal muscle. Enhanced mitochondrial functions in muscle are central to exercise-induced adaptations. However, regular exercise also benefits the brain and is a major protective factor against neurodegenerative diseases, such as the most common age-related form of dementia, Alzheimer's disease, or the most common neurodegenerative motor disorder, Parkinson's disease. While there is evidence that exercise induces signalling from skeletal muscle to the brain, the mechanistic understanding of the crosstalk along the muscle-brain axis is incompletely understood. Mitochondria in both organs, however, seem to be central players. Here, we provide an overview on the central role of mitochondria in exercise-induced communication routes from muscle to the brain. These routes include circulating factors, such as myokines, the release of which often depends on mitochondria, and possibly direct mitochondrial transfer. On this basis, we examine the reported effects of different modes of exercise on mitochondrial features and highlight their expected benefits with regard to neurodegeneration prevention or mitigation. In addition, knowledge gaps in our current understanding related to the muscle-brain axis in neurodegenerative diseases are outlined.


Assuntos
Encéfalo/metabolismo , Suscetibilidade a Doenças , Músculo Esquelético/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Citocinas/metabolismo , Metabolismo Energético , Exercício Físico , Humanos , Mitocôndrias , Dinâmica Mitocondrial , Doenças Neurodegenerativas/patologia , Neuroproteção , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
9.
Nat Commun ; 12(1): 4293, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257294

RESUMO

Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca2+, inhibits halothane- and isoflurane-induced Ca2+ release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Cálcio/metabolismo , Hipertermia Maligna/tratamento farmacológico , Hipertermia Maligna/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Halotano/farmacologia , Isoflurano/farmacologia , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Mutação/genética
10.
Int J Mol Sci ; 22(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34281257

RESUMO

The modern lifestyle brings both excessive fructose consumption and daily exposure to stress which could lead to metabolic disturbances and type 2 diabetes. Muscles are important points of glucose and lipid metabolism, with a crucial role in the maintenance of systemic energy homeostasis. We investigated whether 9-week fructose-enriched diet, with and without exposure to 4-week unpredictable stress, disturbs insulin signaling in the skeletal muscle of male rats and evaluated potential contributory roles of muscle lipid metabolism, glucocorticoid signaling and inflammation. The combination of fructose-enriched diet and stress increased peroxisome proliferator-activated receptors-α and -δ and stimulated lipid uptake, lipolysis and ß-oxidation in the muscle of fructose-fed stressed rats. Combination of treatment also decreased systemic insulin sensitivity judged by lower R-QUICKI, and lowered muscle protein content and stimulatory phosphorylations of insulin receptor supstrate-1 and Akt, as well as the level of 11ß-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor. At the same time, increased levels of protein tyrosine phosphatase-1B, nuclear factor-κB, tumor necrosis factor-α, were observed in the muscle of fructose-fed stressed rats. Based on these results, we propose that decreased glucocorticoid signaling in the skeletal muscle can make a setting for lipid-induced inflammation and the development of insulin resistance in fructose-fed stressed rats.


Assuntos
Frutose/administração & dosagem , Glucocorticoides/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Estresse Fisiológico/fisiologia , Animais , Frutose/efeitos adversos , Humanos , Inflamação/etiologia , Resistência à Insulina/fisiologia , Masculino , Modelos Biológicos , Ratos , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais
11.
J Int Soc Sports Nutr ; 18(1): 54, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238308

RESUMO

BACKGROUND: Recent studies in rodents indicate that a combination of exercise training and supplementation with nicotinamide adenine dinucleotide (NAD+) precursors has synergistic effects. However, there are currently no human clinical trials analyzing this. OBJECTIVE: This study investigates the effects of a combination of exercise training and supplementation with nicotinamide mononucleotide (NMN), the immediate precursor of NAD+, on cardiovascular fitness in healthy amateur runners. METHODS: A six-week randomized, double-blind, placebo-controlled, four-arm clinical trial including 48 young and middle-aged recreationally trained runners of the Guangzhou Pearl River running team was conducted. The participants were randomized into four groups: the low dosage group (300 mg/day NMN), the medium dosage group (600 mg/day NMN), the high dosage group (1200 mg/day NMN), and the control group (placebo). Each group consisted of ten male participants and two female participants. Each training session was 40-60 min, and the runners trained 5-6 times each week. Cardiopulmonary exercise testing was performed at baseline and after the intervention, at 6 weeks, to assess the aerobic capacity of the runners. RESULTS: Analysis of covariance of the change from baseline over the 6 week treatment showed that the oxygen uptake (VO2), percentages of maximum oxygen uptake (VO2max), power at first ventilatory threshold, and power at second ventilatory threshold increased to a higher degree in the medium and high dosage groups compared with the control group. However, there was no difference in VO2max, O2-pulse, VO2 related to work rate, and peak power after the 6 week treatment from baseline in any of these groups. CONCLUSION: NMN increases the aerobic capacity of humans during exercise training, and the improvement is likely the result of enhanced O2 utilization of the skeletal muscle. TRIAL REGISTRATION NUMBER: ChiCTR2000035138 .


Assuntos
Suplementos Nutricionais , Tolerância ao Exercício/fisiologia , Mononucleotídeo de Nicotinamida/administração & dosagem , Consumo de Oxigênio/fisiologia , Condicionamento Físico Humano/métodos , Corrida/fisiologia , Adulto , Ciclismo , Composição Corporal , Método Duplo-Cego , Teste de Esforço/métodos , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , NAD , Mononucleotídeo de Nicotinamida/metabolismo , Condicionamento Físico Humano/estatística & dados numéricos , Placebos/administração & dosagem , Fatores de Tempo
12.
J Int Soc Sports Nutr ; 18(1): 56, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246303

RESUMO

BACKGROUND: The effects of low muscle glycogen on molecular markers of protein synthesis and myogenesis before and during aerobic exercise with carbohydrate ingestion is unclear. The purpose of this study was to determine the effects of initiating aerobic exercise with low muscle glycogen on mTORC1 signaling and markers of myogenesis. METHODS: Eleven men completed two cycle ergometry glycogen depletion trials separated by 7-d, followed by randomized isocaloric refeeding for 24-h to elicit low (LOW; 1.5 g/kg carbohydrate, 3.0 g/kg fat) or adequate (AD; 6.0 g/kg carbohydrate, 1.0 g/kg fat) glycogen. Participants then performed 80-min of cycle ergometry (64 ± 3% VO2peak) while ingesting 146 g carbohydrate. mTORC1 signaling (Western blotting) and gene transcription (RT-qPCR) were determined from vastus lateralis biopsies before glycogen depletion (baseline, BASE), and before (PRE) and after (POST) exercise. RESULTS: Regardless of treatment, p-mTORC1Ser2448, p-p70S6KSer424/421, and p-rpS6Ser235/236 were higher (P < 0.05) POST compared to PRE and BASE. PAX7 and MYOGENIN were lower (P < 0.05) in LOW compared to AD, regardless of time, while MYOD was lower (P < 0.05) in LOW compared to AD at PRE, but not different at POST. CONCLUSION: Initiating aerobic exercise with low muscle glycogen does not affect mTORC1 signaling, yet reductions in gene expression of myogenic regulatory factors suggest that muscle recovery from exercise may be reduced.


Assuntos
Metabolismo dos Carboidratos , Exercício Físico/fisiologia , Glicogênio/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Adulto , Biomarcadores/sangue , Metabolismo dos Carboidratos/genética , Estudos Cross-Over , Ergometria/métodos , Glicogênio/deficiência , Humanos , Masculino , Proteína MyoD/metabolismo , Miogenina/metabolismo , Fator de Transcrição PAX7/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Fatores de Tempo , Transcrição Genética , Adulto Jovem
13.
Sci Total Environ ; 783: 147130, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34088150

RESUMO

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.


Assuntos
Hipóxia , Transcriptoma , Animais , Arvicolinae/genética , Metabolismo Energético , Feminino , Camundongos , Músculo Esquelético/metabolismo
14.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071457

RESUMO

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.


Assuntos
Citocinas/metabolismo , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia
15.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071589

RESUMO

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.


Assuntos
Capilares/fisiopatologia , Complemento C3/deficiência , Isquemia/fisiopatologia , Leucócitos/metabolismo , Músculo Esquelético/fisiopatologia , Animais , Capilares/metabolismo , Complemento C3/genética , Modelos Animais de Doenças , Imunofluorescência/métodos , Humanos , Isquemia/genética , Ativação de Macrófagos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Infiltração de Neutrófilos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo
16.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072258

RESUMO

Mutations in striated preferentially expressed protein kinase (SPEG), a member of the myosin light chain kinase protein family, are associated with centronuclear myopathy (CNM), cardiomyopathy, or a combination of both. Burgeoning evidence suggests that SPEG plays critical roles in the development, maintenance, and function of skeletal and cardiac muscles. Here we review the genotype-phenotype relationships and the molecular mechanisms of SPEG-related diseases. This review will focus on the progress made toward characterizing SPEG and its interacting partners, and its multifaceted functions in muscle regeneration, triad development and maintenance, and excitation-contraction coupling. We will also discuss future directions that are yet to be investigated including understanding of its tissue-specific roles, finding additional interacting proteins and their relationships. Understanding the basic mechanisms by which SPEG regulates muscle development and function will provide critical insights into these essential processes and help identify therapeutic targets in SPEG-related disorders.


Assuntos
Suscetibilidade a Doenças , Expressão Gênica , Desenvolvimento Muscular , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Proteínas de Transporte/metabolismo , Acoplamento Excitação-Contração/genética , Regulação da Expressão Gênica , Humanos , Desenvolvimento Muscular/genética , Proteínas Musculares/química , Músculo Esquelético/metabolismo , Mutação , Miocárdio/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Isoformas de Proteínas , Proteínas Serina-Treonina Quinases/química , Regeneração/genética , Transdução de Sinais , Relação Estrutura-Atividade
17.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068459

RESUMO

Polyphenols are naturally derived compounds that are increasingly being explored for their various health benefits. In fact, foods that are rich in polyphenols have become an attractive source of nutrition and a potential therapeutic strategy to alleviate the untoward effects of metabolic disorders. The last decade has seen a rapid increase in studies reporting on the bioactive properties of polyphenols against metabolic complications, especially in preclinical models. Various experimental models involving cell cultures exposed to lipid overload and rodents on high fat diet have been used to investigate the ameliorative effects of various polyphenols against metabolic anomalies. Here, we systematically searched and included literature reporting on the impact of polyphenols against metabolic function, particularly through the modulation of mitochondrial bioenergetics within the skeletal muscle. This is of interest since the skeletal muscle is rich in mitochondria and remains one of the main sites of energy homeostasis. Notably, increased substrate availability is consistent with impaired mitochondrial function and enhanced oxidative stress in preclinical models of metabolic disease. This explains the general interest in exploring the antioxidant properties of polyphenols and their ability to improve mitochondrial function. The current review aimed at understanding how these compounds modulate mitochondrial bioenergetics to improve metabolic function in preclinical models on metabolic disease.


Assuntos
Músculo Esquelético/metabolismo , Polifenóis/farmacologia , Animais , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Humanos , Músculo Esquelético/efeitos dos fármacos , Polifenóis/química
18.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067866

RESUMO

Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.


Assuntos
Anexinas/metabolismo , Proteínas de Membrana/metabolismo , Distrofias Musculares/metabolismo , Anexina A1/metabolismo , Anexina A1/fisiologia , Anexinas/fisiologia , Membrana Celular/metabolismo , Humanos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Distrofias Musculares/fisiopatologia
19.
Nutrients ; 13(5)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069950

RESUMO

Insulin resistance is a key etiological factor in promoting not only type 2 diabetes mellitus but also cardiovascular disease (CVD). Exercise is a first-line therapy for combating chronic disease by improving insulin action through, in part, reducing hepatic glucose production and lipolysis as well as increasing skeletal muscle glucose uptake and vasodilation. Just like a pharmaceutical agent, exercise can be viewed as a "drug" such that identifying an optimal prescription requires a determination of mode, intensity, and timing as well as consideration of how much exercise is done relative to sitting for prolonged periods (e.g., desk job at work). Furthermore, proximal nutrition (nutrient timing, carbohydrate intake, etc.), sleep (or lack thereof), as well as alcohol consumption are likely important considerations for enhancing adaptations to exercise. Thus, identifying the maximal exercise "drug" for reducing insulin resistance will require a multi-health behavior approach to optimize type 2 diabetes and CVD care.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Ingestão de Energia/fisiologia , Exercício Físico/fisiologia , Resistência à Insulina/fisiologia , Sono/fisiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Metabolismo dos Carboidratos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Metabolismo Energético , Glucose/biossíntese , Humanos , Lipólise , Fígado/metabolismo , Músculo Esquelético/metabolismo , Vasodilatação/fisiologia
20.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072147

RESUMO

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from Salvia officinalis L. (common Sage, Lamiaceae) possesses high activity against Trypanosoma brucei rhodesiense (Tbr), causative agent of East African Human Trypanosomiasis. We have now investigated in detail the antitrypanosomal constituents of this preparation. A variety of fractions were tested for antitrypanosomal activity and analyzed by UHPLC/+ESI QqTOF MS. The resulting data were used to generate a partial least squares (PLS) regression model that highlighted eight particular constituents that were likely to account for the major part of the bioactivity. These compounds were then purified and identified and their activity against the pathogen tested. All identified compounds (one flavonoid and eight diterpenes) displayed significant activity against Tbr, in some cases higher than that of the total tincture. From the overall results, it can be concluded that the antitrypanosomal activity of S. officinalis L. is, for the major part, caused by abietane-type diterpenes of the rosmanol/rosmaquinone group.


Assuntos
Antiprotozoários/farmacologia , Salvia officinalis/metabolismo , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Abietanos/química , Animais , Calibragem , Cromatografia Líquida de Alta Pressão , Diterpenos/química , Flavonoides/química , Concentração Inibidora 50 , Análise dos Mínimos Quadrados , Espectroscopia de Ressonância Magnética , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Testes de Sensibilidade Parasitária , Extratos Vegetais , Preparações de Plantas/farmacologia , Plantas Medicinais , Ratos , Espectrometria de Massas por Ionização por Electrospray , Tripanossomíase/parasitologia
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