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1.
FASEB J ; 35(10): e21905, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34569672

RESUMO

The study was aimed at investigating the mechanisms and structures which determine mechanical properties of skeletal muscles under gravitational unloading and plantar mechanical stimulation (PMS). We hypothesized that PMS would increase NO production and prevent an unloading-induced reduction in skeletal muscle passive stiffness. Wistar rats were hindlimb suspended and subjected to a daily PMS and one group of stimulated animals was also treated with nitric oxide synthase (NOS) inhibitor (L-NAME). Animals received mechanical stimulation of the feet for 4 h a day throughout 7-day hindlimb suspension (HS) according to a scheme that mimics the normal walking of the animal. Seven-day HS led to a significant reduction in soleus muscle weight by 25%. However, PMS did not prevent the atrophic effect induced by HS. Gravitational unloading led to a significant decrease in maximum isometric force and passive stiffness by 38% and 31%, respectively. The use of PMS prevented a decrease in the maximum isometric strength of the soleus muscle. At the same time, the passive stiffness of the soleus in the PMS group significantly exceeded the control values by 40%. L-NAME (NOS inhibitor) administration attenuated the effect of PMS on passive stiffness and maximum force of the soleus muscle. The content of the studied cytoskeletal proteins (α-actinin-2, α-actinin-3, desmin, titin, nebulin) decreased after 7-day HS, but this decrease was successfully prevented by PMS in a NOS-dependent manner. We also observed significant decreases in mRNA expression levels of α-actinin-2, desmin, and titin after HS, which was prevented by PMS. The study also revealed a significant NOS-dependent effect of PMS on the content of collagen-1a, but not collagen-3a. Thus, PMS during mechanical unloading is able to maintain soleus muscle passive tension and force as well as mRNA transcription and protein contents of cytoskeletal proteins in a NOS-dependent manner.


Assuntos
Proteínas do Citoesqueleto/biossíntese , Elevação dos Membros Posteriores , Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Óxido Nítrico Sintase/metabolismo , Animais , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Wistar
2.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443492

RESUMO

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.


Assuntos
Caquexia/etiologia , Caquexia/fisiopatologia , Curcumina/farmacologia , Músculos/patologia , Músculos/fisiopatologia , Neoplasias/complicações , Proteólise , Resveratrol/farmacologia , Animais , Biomarcadores/metabolismo , Linhagem Celular , Feminino , Camundongos Endogâmicos BALB C , Proteínas Musculares/metabolismo , Músculos/efeitos dos fármacos , Atrofia Muscular/metabolismo , Fenótipo , Proteólise/efeitos dos fármacos , Transdução de Sinais , Sirtuína 1/metabolismo
3.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443483

RESUMO

Skeletal muscle atrophy is the decrease in muscle mass and strength caused by reduced protein synthesis/accelerated protein degradation. Various conditions, such as denervation, disuse, aging, chronic diseases, heart disease, obstructive lung disease, diabetes, renal failure, AIDS, sepsis, cancer, and steroidal medications, can cause muscle atrophy. Mechanistically, inflammation, oxidative stress, and mitochondrial dysfunction are among the major contributors to muscle atrophy, by modulating signaling pathways that regulate muscle homeostasis. To prevent muscle catabolism and enhance muscle anabolism, several natural and synthetic compounds have been investigated. Recently, polyphenols (i.e., natural phytochemicals) have received extensive attention regarding their effect on muscle atrophy because of their potent antioxidant and anti-inflammatory properties. Numerous in vitro and in vivo studies have reported polyphenols as strongly effective bioactive molecules that attenuate muscle atrophy and enhance muscle health. This review describes polyphenols as promising bioactive molecules that impede muscle atrophy induced by various proatrophic factors. The effects of each class/subclass of polyphenolic compounds regarding protection against the muscle disorders induced by various pathological/physiological factors are summarized in tabular form and discussed. Although considerable variations in antiatrophic potencies and mechanisms were observed among structurally diverse polyphenolic compounds, they are vital factors to be considered in muscle atrophy prevention strategies.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Compostos Fitoquímicos/farmacologia , Polifenóis/farmacologia , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antioxidantes/efeitos adversos , Antioxidantes/química , Antioxidantes/uso terapêutico , Humanos , Compostos Fitoquímicos/efeitos adversos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Polifenóis/efeitos adversos , Polifenóis/química , Polifenóis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
4.
Nutrients ; 13(7)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34371808

RESUMO

Endoplasmic reticulum stress (ERS) and autophagy pathways are implicated in disuse muscle atrophy. The effects of high eicosapentaenoic (EPA) or high docosahexaenoic (DHA) fish oils on soleus muscle ERS and autophagy markers were investigated in a rat hindlimb suspension (HS) atrophy model. Adult Wistar male rats received daily by gavage supplementation (0.3 mL per 100 g b.w.) of mineral oil or high EPA or high DHA fish oils (FOs) for two weeks. Afterward, the rats were subjected to HS and the respective treatments concomitantly for an additional two-week period. After four weeks, we evaluated ERS and autophagy markers in the soleus muscle. Results were analyzed using two-way analysis of variance (ANOVA) and Bonferroni post hoc test. Gastrocnemius muscle ω-6/ω-3 fatty acids (FAs) ratio was decreased by both FOs indicating the tissue incorporation of omega-3 fatty acids. HS altered (p < 0.05) the protein content (decreasing total p38 and BiP and increasing p-JNK2/total JNK2 ratio, and caspase 3) and gene expressions (decreasing BiP and increasing IRE1 and PERK) of ERS and autophagy (decreasing Beclin and increasing LC3 and ATG14) markers in soleus. Both FOs attenuated (p < 0.05) the increase in PERK and ATG14 expressions induced by HS. Thus, both FOs could potentially attenuate ERS and autophagy in skeletal muscles undergoing atrophy.


Assuntos
Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Óleos de Peixe/farmacologia , Músculo Esquelético/metabolismo , Atrofia Muscular/terapia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Elevação dos Membros Posteriores , Masculino , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Ratos , Ratos Wistar
5.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360534

RESUMO

Inorganic phosphate (Pi) is an essential nutrient for living organisms and is maintained in equilibrium in the range of 0.8-1.4 mM Pi. Pi is a source of organic constituents for DNA, RNA, and phospholipids and is essential for ATP formation mainly through energy metabolism or cellular signalling modulators. In mitochondria isolated from the brain, liver, and heart, Pi has been shown to induce mitochondrial reactive oxygen species (ROS) release. Therefore, the purpose of this review article was to gather relevant experimental records of the production of Pi-induced reactive species, mainly ROS, to examine their essential roles in physiological processes, such as the development of bone and cartilage and the development of diseases, such as cardiovascular disease, diabetes, muscle atrophy, and male reproductive system impairment. Interestingly, in the presence of different antioxidants or inhibitors of cytoplasmic and mitochondrial Pi transporters, Pi-induced ROS production can be reversed and may be a possible pharmacological target.


Assuntos
Doenças Cardiovasculares/patologia , Diabetes Mellitus/patologia , Mitocôndrias/patologia , Atrofia Muscular/patologia , Fosfatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Metabolismo Energético , Humanos , Mitocôndrias/efeitos dos fármacos , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo
6.
Nutrients ; 13(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34371902

RESUMO

There is ongoing debate as to whether or not α-hydroxyisocaproic acid (HICA) positively regulates skeletal muscle protein synthesis resulting in the gain or maintenance of skeletal muscle. We investigated the effects of HICA on mouse C2C12 myotubes under normal conditions and during cachexia induced by co-exposure to TNFα and IFNγ. The phosphorylation of AMPK or ERK1/2 was significantly altered 30 min after HICA treatment under normal conditions. The basal protein synthesis rates measured by a deuterium-labeling method were significantly lowered by the HICA treatment under normal and cachexic conditions. Conversely, myotube atrophy induced by TNFα/IFNγ co-exposure was significantly improved by the HICA pretreatment, and this improvement was accompanied by the inhibition of iNOS expression and IL-6 production. Moreover, HICA also suppressed the TNFα/IFNγ co-exposure-induced secretion of 3-methylhistidine. These results demonstrated that HICA decreases basal protein synthesis under normal or cachexic conditions; however, HICA might attenuate skeletal muscle atrophy via maintaining a low level of protein degradation under cachexic conditions.


Assuntos
Caquexia/tratamento farmacológico , Caproatos/farmacologia , Interferon gama/toxicidade , Interleucina-6/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Caquexia/induzido quimicamente , Caquexia/metabolismo , Caquexia/patologia , Linhagem Celular , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Metilistidinas/metabolismo , Camundongos , Fibras Musculares Esqueléticas/enzimologia , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Fosforilação , Biossíntese de Proteínas , Proteólise
7.
Am J Physiol Cell Physiol ; 321(3): C559-C568, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34319830

RESUMO

In organisms from flies to mammals, the initial formation of a functional tendon is completely dependent on chemical signals from muscles (myokines). However, how myokines affect the maturation, maintenance, and regeneration of tendons as a function of age is completely unstudied. Here we discuss the role of four myokines-fibroblast growth factors (FGF), myostatin, the secreted protein acidic and rich in cysteine (SPARC) miR-29-in tendon development and hypothesize a role for these factors in the progressive changes in tendon structure and function as a result of muscle wasting (disuse, aging, and disease). Because of the close relationship between mechanical loading and muscle and tendon regulation, disentangling muscle-tendon cross talk from simple mechanical loading is experimentally quite difficult. Therefore, we propose an experimental framework that hopefully will be useful in demonstrating muscle-tendon cross talk in vivo. Though understudied, the promise of a better understanding of muscle-tendon cross talk is the development of new interventions that will improve tendon development, regeneration, and function throughout the lifespan.


Assuntos
Envelhecimento/genética , Exossomos/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Tendões/metabolismo , Envelhecimento/metabolismo , Animais , Fenômenos Biomecânicos , Exossomos/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Musculares/metabolismo , Células Musculares/patologia , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miostatina/genética , Miostatina/metabolismo , Osteonectina/genética , Osteonectina/metabolismo , Transdução de Sinais , Tendões/patologia
8.
DNA Cell Biol ; 40(9): 1167-1176, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34255539

RESUMO

Skeletal muscle has great plasticity. An increase in protein degradation can cause muscle atrophy. Atrogin-1 and muscle ring finger-1 (MuRF1) are dramatically upregulated in various muscle atrophy. Inhibition of Atrogin-1 and MuRF1 protects against muscle atrophy. MiR-29 plays an important regulatory role in skeletal muscle development. However, the function of miR-29 in skeletal muscle protein metabolism is not clear. To investigate the function of miR-29, we generated miR-29 knockout mice and the miR-29ab1 cluster overexpression mice. The disruption of miR-29 led to severe atrophy of skeletal muscle during puberty, and the muscle-specific overexpression of the miR-29ab1 cluster protected against denervation-induced and fasting-induced muscle atrophy. Furthermore, the overexpression of miR-29a, b mimics in myotubes resisted the muscle atrophy. MuRF1 was the direct target gene of miR-29a, b. These results demonstrate that miR-29ab1 cluster plays a critical role in the maintenance of skeletal muscle. MiR-29ab1 cluster is the excellent inhibitor of MuRF1, ultimately indicating that miR-29ab1 cluster is good therapeutic molecule candidate for adulthood.


Assuntos
MicroRNAs/fisiologia , Desenvolvimento Muscular , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Mioblastos
9.
Am J Physiol Regul Integr Comp Physiol ; 321(3): R413-R428, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34260302

RESUMO

Elephant seals experience natural periods of prolonged food deprivation while breeding, molting, and undergoing postnatal development. Prolonged food deprivation in elephant seals increases circulating glucocorticoids without inducing muscle atrophy, but the cellular mechanisms that allow elephant seals to cope with such conditions remain elusive. We generated a cellular model and conducted transcriptomic, metabolic, and morphological analyses to study how seal cells adapt to sustained glucocorticoid exposure. Seal muscle progenitor cells differentiate into contractile myotubes with a distinctive morphology, gene expression profile, and metabolic phenotype. Exposure to dexamethasone at three ascending concentrations for 48 h modulated the expression of six clusters of genes related to structural constituents of muscle and pathways associated with energy metabolism and cell survival. Knockdown of the glucocorticoid receptor (GR) and downstream expression analyses corroborated that GR mediates the observed effects. Dexamethasone also decreased cellular respiration, shifted the metabolic phenotype toward glycolysis, and induced mitochondrial fission and dissociation of mitochondria-endoplasmic reticulum (ER) interactions without decreasing cell viability. Knockdown of DNA damage-inducible transcript 4 (DDIT4), a GR target involved in the dissociation of mitochondria-ER membranes, recovered respiration and modulated antioxidant gene expression in myotubes treated with dexamethasone. These results show that adaptation to sustained glucocorticoid exposure in elephant seal myotubes involves a metabolic shift toward glycolysis, which is supported by alterations in mitochondrial morphology and a reduction in mitochondria-ER interactions, resulting in decreased respiration without compromising cell survival.


Assuntos
Metabolismo Energético/fisiologia , Glucocorticoides/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Adaptação Fisiológica , Animais , Antioxidantes/metabolismo , Jejum/metabolismo , Privação de Alimentos/fisiologia , Fenótipo , Receptores de Glucocorticoides/genética , Focas Verdadeiras/metabolismo , Transcriptoma/fisiologia
10.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298968

RESUMO

Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells.


Assuntos
Cardiomiopatias/genética , Coração/fisiopatologia , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Doenças Neuromusculares/genética , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Modelos Animais de Doenças , Metabolismo Energético , Humanos , Camundongos , Mitocôndrias Cardíacas/metabolismo , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Proteínas Musculares/fisiologia , Músculo Esquelético/ultraestrutura , Atrofia Muscular/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/patologia , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/patologia , Fenótipo
11.
FASEB J ; 35(8): e21821, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34325487

RESUMO

Skeletal muscle atrophy is a debilitating complication of many chronic disease states and disuse conditions including denervation. However, molecular and signaling mechanisms of muscle wasting remain less understood. Here, we demonstrate that the levels of several toll-like receptors (TLRs) and their downstream signaling adaptor, myeloid differentiation primary response 88 (MyD88), are induced in skeletal muscle of mice in response to sciatic nerve denervation. Muscle-specific ablation of MyD88 mitigates denervation-induced skeletal muscle atrophy in mice. Targeted ablation of MyD88 suppresses the components of ubiquitin-proteasome system, autophagy, and FOXO transcription factors in skeletal muscle during denervation. We also found that specific inhibition of MyD88 reduces the activation of canonical nuclear factor-kappa (NF-κB) pathway and expression of receptors for inflammatory cytokines in denervated muscle. In contrast, inhibition of MyD88 stimulates the activation of non-canonical NF-κB signaling in denervated skeletal muscle. Ablation of MyD88 also inhibits the denervation-induced increase in phosphorylation of AMPK without having any effect on the phosphorylation of mTOR. Moreover, targeted ablation of MyD88 inhibits the activation of a few components of the unfolded protein response (UPR) pathways, especially X-box protein 1 (XBP1). Importantly, myofiber-specific ablation of XBP1 mitigates denervation-induced skeletal muscle atrophy in mice. Collectively, our experiments suggest that TLR-MyD88 signaling mediates skeletal muscle wasting during denervation potentially through the activation of canonical NF-κB signaling, AMPK and UPR pathways.


Assuntos
Músculo Esquelético/inervação , Atrofia Muscular/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Animais , Biomarcadores/sangue , Estresse do Retículo Endoplasmático/fisiologia , Regulação da Expressão Gênica/fisiologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Resposta a Proteínas não Dobradas
12.
Nutrients ; 13(6)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199575

RESUMO

Imbalance of protein homeostasis, with excessive protein degradation compared with protein synthesis, leads to the development of muscle atrophy resulting in a decrease in muscle mass and consequent muscle weakness and disability. Potential triggers of muscle atrophy include inflammation, malnutrition, aging, cancer, and an unhealthy lifestyle such as sedentariness and high fat diet. Nutraceuticals with preventive and therapeutic effects against muscle atrophy have recently received increasing attention since they are potentially more suitable for long-term use. The implementation of nutraceutical intervention might aid in the development and design of precision medicine strategies to reduce the burden of muscle atrophy. In this review, we will summarize the current knowledge on the importance of nutraceuticals in the prevention of skeletal muscle mass loss and recovery of muscle function. We also highlight the cellular and molecular mechanisms of these nutraceuticals and their possible pharmacological use, which is of great importance for the prevention and treatment of muscle atrophy.


Assuntos
Suplementos Nutricionais , Atrofia Muscular/prevenção & controle , Atrofia Muscular/terapia , Aminoácidos , Animais , Bases de Dados Factuais , Ácidos Graxos , Humanos , Inflamação/metabolismo , Minerais , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Peptídeos , Compostos Fitoquímicos , Probióticos , Proteínas , Proteólise , Vitaminas
13.
J Clin Invest ; 131(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34060483

RESUMO

Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of pro-cachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.


Assuntos
Caquexia/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Insuficiência Renal Crônica/metabolismo , Síndrome de Emaciação/metabolismo , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Ativinas/genética , Ativinas/metabolismo , Animais , Caquexia/etiologia , Caquexia/genética , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Atrofia Muscular/etiologia , Atrofia Muscular/genética , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Síndrome de Emaciação/etiologia , Síndrome de Emaciação/genética
14.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063397

RESUMO

The Cellular Communication Network (CCN) family of matricellular proteins comprises six proteins that share conserved structural features and play numerous biological roles. These proteins can interact with several receptors or soluble proteins, regulating cell signaling pathways in various tissues under physiological and pathological conditions. In the skeletal muscle of mammals, most of the six CCN family members are expressed during embryonic development or in adulthood. Their roles during the adult stage are related to the regulation of muscle mass and regeneration, maintaining vascularization, and the modulation of skeletal muscle fibrosis. This work reviews the CCNs proteins' role in skeletal muscle physiology and disease, focusing on skeletal muscle fibrosis and its regulation by Connective Tissue Growth factor (CCN2/CTGF). Furthermore, we review evidence on the modulation of fibrosis and CCN2/CTGF by the renin-angiotensin system and the kallikrein-kinin system of vasoactive peptides.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Músculo Esquelético/fisiologia , Peptídeos/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Cininas/metabolismo , Família Multigênica , Proteínas Musculares/metabolismo , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Regeneração , Sistema Renina-Angiotensina
15.
Genes (Basel) ; 12(5)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063658

RESUMO

Skeletal muscle atrophy in an inevitable occurrence with advancing age, and a consequence of disease including cancer. Muscle atrophy in the elderly is managed by a regimen of resistance exercise and increased protein intake. Understanding the signaling that regulates muscle mass may identify potential therapeutic targets for the prevention and reversal of muscle atrophy in metabolic and neuromuscular diseases. This review covers the major anabolic and catabolic pathways that regulate skeletal muscle mass, with a focus on recent progress and potential new players.


Assuntos
Envelhecimento/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Transdução de Sinais , Envelhecimento/patologia , Animais , Humanos , Hipertrofia , Músculo Esquelético/crescimento & desenvolvimento , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
16.
Am J Physiol Cell Physiol ; 321(1): C40-C57, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33950699

RESUMO

Skeletal muscle is the most abundant tissue in healthy individuals and it has important roles in health beyond voluntary movement. The overall mass and energy requirements of skeletal muscle require it to be metabolically active and flexible to multiple energy substrates. The tissue has evolved to be largely load dependent and it readily adapts in a number of positive ways to repetitive overload, such as various forms of exercise training. However, unloading from extended bed rest and/or metabolic derangements in response to trauma, acute illness, or severe pathology, commonly results in rapid muscle wasting. Decline in muscle mass contributes to multimorbidity, reduces function, and exerts a substantial, negative impact on the quality of life. The principal mechanisms controlling muscle mass have been well described and these cellular processes are intricately regulated by exercise. Accordingly, exercise has shown great promise and efficacy in preventing or slowing muscle wasting through changes in molecular physiology, organelle function, cell signaling pathways, and epigenetic regulation. In this review, we focus on the role of exercise in altering the molecular landscape of skeletal muscle in a manner that improves or maintains its health and function in the presence of unloading or disease.epigenetics; exercise; muscle wasting; resistance training; skeletal muscle.


Assuntos
Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/prevenção & controle , Biossíntese de Proteínas , Treinamento de Força/métodos , Sepse/metabolismo , Adaptação Fisiológica , Animais , Repouso em Cama/efeitos adversos , Queimaduras/genética , Queimaduras/metabolismo , Queimaduras/patologia , Queimaduras/reabilitação , Epigênese Genética , Humanos , Denervação Muscular/reabilitação , Proteínas Musculares/biossíntese , Músculo Esquelético/lesões , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Proteólise , Qualidade de Vida/psicologia , Comportamento Sedentário , Sepse/microbiologia , Sepse/patologia , Sepse/reabilitação , Transdução de Sinais , Ausência de Peso/efeitos adversos
17.
J Clin Invest ; 131(9)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33938454

RESUMO

Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. Considerable progress has been made in elucidating key components of this regulatory system, and in parallel with this effort has been the development of numerous biologics that have been tested in clinical trials for a wide range of indications, including muscular dystrophy, sporadic inclusion body myositis, spinal muscular atrophy, cachexia, muscle loss due to aging or following falls, obesity, and type 2 diabetes. Here, I review what is known about the MSTN regulatory system and the current state of efforts to target this pathway for clinical applications.


Assuntos
Envelhecimento , Diabetes Mellitus Tipo 2 , Atrofia Muscular , Doenças Musculares , Miostatina , Obesidade , Transdução de Sinais/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Doenças Musculares/genética , Doenças Musculares/metabolismo , Miostatina/genética , Miostatina/metabolismo , Obesidade/genética , Obesidade/metabolismo
18.
Mol Med Rep ; 24(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33955507

RESUMO

The protein extracted from red algae Pyropia yezoensis has various biological activities, including anti­inflammatory, anticancer, antioxidant, and antiobesity properties. However, the effects of P. yezoensis protein (PYCP) on tumor necrosis factor­α (TNF­α)­induced muscle atrophy are unknown. Therefore, the present study investigated the protective effects and related mechanisms of PYCP against TNF­α­induced myotube atrophy in C2C12 myotubes. Treatment with TNF­α (20 ng/ml) for 48 h significantly reduced myotube viability and diameter and increased intracellular reactive oxygen species levels; these effects were significantly reversed in a dose­dependent manner following treatment with 25­100 µg/ml PYCP. PYCP inhibited the expression of TNF receptor­1 in TNF­α­induced myotubes. In addition, PYCP markedly downregulated the nuclear translocation of nuclear factor­κB (NF­κB) by inhibiting the phosphorylation of inhibitor of κB. Furthermore, PYCP treatment suppressed 20S proteasome activity, IL­6 production, and the expression of the E3 ubiquitin ligases, atrogin­1/muscle atrophy F­box and muscle RING­finger protein­1. Finally, PYCP treatment increased the protein expression levels of myoblast determination protein 1 and myogenin in TNF­α­induced myotubes. The present findings indicate that PYCP may protect against TNF­α­induced myotube atrophy by inhibiting the proinflammatory NF­κB pathway.


Assuntos
Proteínas de Algas/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Substâncias Protetoras/farmacologia , Rodófitas/química , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Interleucina-6/metabolismo , Camundongos , Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Proteína MyoD/metabolismo , Miogenina/metabolismo , NF-kappa B/metabolismo , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
20.
Am J Physiol Cell Physiol ; 321(1): C26-C37, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33909501

RESUMO

In vitro models of muscle aging are useful for understanding mechanisms of age-related muscle loss and aiding the development of targeted therapies. To investigate mechanisms of age-related muscle loss in vitro utilizing ex vivo human serum, fasted blood samples were obtained from four old (72 ± 1 yr) and four young (26 ± 3 yr) men. Older individuals had elevated levels of plasma CRP, IL-6, HOMA-IR, and lower concentric peak torque and work-per-repetition compared with young participants (P < 0.05). C2C12 myotubes were serum and amino acid starved for 1 h and conditioned with human serum (10%) for 4 h or 24 h. After 4 h, C2C12 cells were treated with 5 mM leucine for 30 min. Muscle protein synthesis (MPS) was determined through the surface sensing of translation (SUnSET) technique and regulatory signaling pathways were measured via Western blot. Myotube diameter was significantly reduced in myotubes treated with serum from old, in comparison to young donors (84%, P < 0.001). MPS was reduced in myotubes treated with old donor serum, compared with young serum before leucine treatment (32%, P < 0.01). MPS and the phosphorylation of Akt, p70S6K, and eEF2 were increased in myotubes treated with young serum in response to leucine treatment, with a blunted response identified in cells treated with old serum (P < 0.05). Muscle protein breakdown signaling pathways did not differ between groups. In summary, we show that myotubes conditioned with serum from older individuals had decreased myotube diameter and MPS compared with younger individuals, potentially driven by low-grade systemic inflammation.


Assuntos
Envelhecimento/genética , Meios de Cultura/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Proteínas Musculares/genética , Biossíntese de Proteínas/efeitos dos fármacos , Adulto , Idoso , Envelhecimento/metabolismo , Animais , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Linhagem Celular , Meios de Cultura/química , Humanos , Resistência à Insulina , Interleucina-6/sangue , Interleucina-6/genética , Leucina/farmacologia , Masculino , Camundongos , Modelos Biológicos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Fator 2 de Elongação de Peptídeos/genética , Fator 2 de Elongação de Peptídeos/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais
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