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Many organisms have developed a robust ability to adapt and survive in the face of environmental perturbations that threaten the integrity of their genome, proteome, or metabolome. Studies in multiple model organisms have shown that, in general, when exposed to stress, cells activate a complex prosurvival signaling network that includes immune and DNA damage response genes, chaperones, antioxidant enzymes, structural proteins, metabolic enzymes, and noncoding RNAs. The manner of activation runs the gamut from transcriptional induction of genes to increased stability of transcripts to posttranslational modification of important biosynthetic proteins within the stressed tissue. Superimposed on these largely autonomous effects are nonautonomous responses in which the stressed tissue secretes peptides and other factors that stimulate tissues in different organs to embark on processes that ultimately help the organism as a whole cope with stress. This review focuses on the mechanisms by which tissues in one organ adapt to environmental challenges by regulating stress responses in tissues of different organs.
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Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Animais , Humanos , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/fisiologiaRESUMO
In animals, the brain regulates feeding behavior in response to local energy demands of peripheral tissues, which secrete orexigenic and anorexigenic hormones. Although skeletal muscle is a key peripheral tissue, it remains unknown whether muscle-secreted hormones regulate feeding. In Drosophila, we found that decapentaplegic (dpp), the homolog of human bone morphogenetic proteins BMP2 and BMP4, is a muscle-secreted factor (a myokine) that is induced by nutrient sensing and that circulates and signals to the brain. Muscle-restricted dpp RNAi promotes foraging and feeding initiation, whereas dpp overexpression reduces it. This regulation of feeding by muscle-derived Dpp stems from modulation of brain tyrosine hydroxylase (TH) expression and dopamine biosynthesis. Consistently, Dpp receptor signaling in dopaminergic neurons regulates TH expression and feeding initiation via the downstream transcriptional repressor Schnurri. Moreover, pharmacologic modulation of TH activity rescues the changes in feeding initiation due to modulation of dpp expression in muscle. These findings indicate that muscle-to-brain endocrine signaling mediated by the myokine Dpp regulates feeding behavior.
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Proteínas de Drosophila/metabolismo , Drosophila/genética , Drosophila/metabolismo , Comportamento Alimentar/fisiologia , Animais , Encéfalo/fisiologia , Proteínas de Ligação a DNA/metabolismo , Dopaminérgicos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Drosophila/enzimologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Levodopa/farmacologia , Monoiodotirosina/farmacologia , Transdução de Sinais , Fatores de Transcrição/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Regulação para CimaRESUMO
Myokines and exosomes, originating from skeletal muscle, are shown to play a significant role in maintaining brain homeostasis. While exercise has been reported to promote muscle secretion, little is known about the effects of neuronal innervation and activity on the yield and molecular composition of biologically active molecules from muscle. As neuromuscular diseases and disabilities associated with denervation impact muscle metabolism, we hypothesize that neuronal innervation and firing may play a pivotal role in regulating secretion activities of skeletal muscles. We examined this hypothesis using an engineered neuromuscular tissue model consisting of skeletal muscles innervated by motor neurons. The innervated muscles displayed elevated expression of mRNAs encoding neurotrophic myokines, such as interleukin-6, brain-derived neurotrophic factor, and FDNC5, as well as the mRNA of peroxisome-proliferator-activated receptor γ coactivator 1α, a key regulator of muscle metabolism. Upon glutamate stimulation, the innervated muscles secreted higher levels of irisin and exosomes containing more diverse neurotrophic microRNAs than neuron-free muscles. Consequently, biological factors secreted by innervated muscles enhanced branching, axonal transport, and, ultimately, spontaneous network activities of primary hippocampal neurons in vitro. Overall, these results reveal the importance of neuronal innervation in modulating muscle-derived factors that promote neuronal function and suggest that the engineered neuromuscular tissue model holds significant promise as a platform for producing neurotrophic molecules.
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Fator Neurotrófico Derivado do Encéfalo , Exossomos , Músculo Esquelético , Exossomos/metabolismo , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/inervação , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Camundongos , Fibronectinas/metabolismo , Neurônios Motores/metabolismo , Interleucina-6/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Neurônios/metabolismo , Fatores de Crescimento Neural/metabolismo , MiocinasRESUMO
Skeletal muscles undergo robust regeneration upon injury, and infiltrating immune cells play a major role in not only clearing damaged tissues but also regulating the myogenic process through secreted cytokines. Chemokine C-C motif ligand 8 (Ccl8), along with Ccl2 and Ccl7, has been reported to mediate inflammatory responses to suppress muscle regeneration. Ccl8 is also expressed by muscle cells, but a role of the muscle cell-derived Ccl8 in myogenesis has not been reported. In this study, we found that knockdown of Ccl8, but not Ccl2 or Ccl7, led to increased differentiation of C2C12 myoblasts. Analysis of existing single-cell transcriptomic datasets revealed that both immune cells and muscle stem cells (MuSCs) in regenerating muscles express Ccl8, with the expression by MuSCs at a much lower level, and that the temporal patterns of Ccl8 expression were different in MuSCs and macrophages. To probe a function of muscle cell-derived Ccl8 in vivo, we utilized a mouse system in which Cas9 was expressed in Pax7+ myogenic progenitor cells (MPCs) and Ccl8 gene editing was induced by AAV9-delivered sgRNA. Depletion of Ccl8 in Pax7+ MPCs resulted in accelerated muscle regeneration after barium chloride-induced injury in both young and middle-aged mice, and intramuscular administration of a recombinant Ccl8 reversed the phenotype. Accelerated regeneration was also observed when Ccl8 was depleted in Myf5+ or MyoD+ MPCs by similar approaches. Our results suggest that muscle cell-derived Ccl8 plays a unique role in regulating the initiation of myogenic differentiation during injury-induced muscle regeneration.
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Diferenciação Celular , Quimiocina CCL8 , Desenvolvimento Muscular , Músculo Esquelético , Mioblastos , Regeneração , Animais , Camundongos , Regeneração/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Músculo Esquelético/lesões , Desenvolvimento Muscular/fisiologia , Quimiocina CCL8/metabolismo , Quimiocina CCL8/genética , Mioblastos/metabolismo , Mioblastos/fisiologia , Camundongos Endogâmicos C57BL , Linhagem Celular , Masculino , Quimiocina CCL7/metabolismo , Quimiocina CCL7/genética , Macrófagos/metabolismoRESUMO
A significant amount of attention has been brought to the endocrine-like function of skeletal muscle on various tissues, particularly with bone. Several lines of investigation indicate that the physiology of both bone and muscle systems may be regulated by a given stimulus, such as exercise, aging, and inactivity. Moreover, emerging evidence indicates that bone is heavily influenced by soluble factors derived from skeletal muscle (i.e., muscle-to-bone communication). The purpose of this review is to discuss the regulation of bone remodeling (formation and/or resorption) through skeletal muscle-derived cytokines (hereafter myokines) including the anti-inflammatory cytokine METRNL and pro-inflammatory cytokines (e.g., TNF-α, IL-6, FGF-2 and others). Our goal is to highlight possible therapeutic opportunities to improve muscle and bone health in aging.
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Exercício Físico , Músculo Esquelético , Osso e Ossos , Citocinas/metabolismo , Exercício Físico/fisiologia , Músculo Esquelético/metabolismoRESUMO
This study aimed to evaluate the role of skeletal muscle-derived interleukin (IL)-15 in the regulation of skeletal muscle autophagy using IL-15 knockout (KO) and transgenic (TG) mice. Male C57BL/6 wild-type (WT), IL-15 KO, and IL-15 TG mice were used in this study. Changes in muscle mass, forelimb grip strength, succinate dehydrogenase (SDH) activity, gene and protein expression levels of major regulators and indicators of autophagy, comprehensive gene expression, and DNA methylation in the gastrocnemius muscle were analyzed. Enrichment pathway analyses revealed that the pathology of IL-15 gene deficiency was related to the autophagosome pathway. Moreover, although IL-15 KO mice maintained gastrocnemius muscle mass, they exhibited a decrease in autophagy induction. IL-15 TG mice exhibited a decrease in gastrocnemius muscle mass and an increase in forelimb grip strength and SDH activity in skeletal muscle. In the gastrocnemius muscle, the ratio of phosphorylated adenosine monophosphate-activated protein kinase α (AMPKα) to total AMPKα and unc-51-like autophagy activating kinase 1 and Beclin1 protein expression were higher in the IL-15 TG group than in the WT group. IL-15 gene deficiency induces a decrease in autophagy induction. In contrast, IL-15 overexpression could improve muscle quality by activating autophagy induction while decreasing muscle mass. The regulation of IL-15 in autophagy in skeletal muscles may lead to the development of therapies for the autophagy-induced regulation of skeletal muscle mass and cellular quality control.NEW & NOTEWORTHY IL-15 gene deficiency can decrease autophagy induction. However, although IL-15 overexpression induced a decrease in muscle mass, it led to an improvement in muscle quality. Based on these results, understanding the role of IL-15 in regulating autophagy pathways within skeletal muscle may lead to the development of therapies for the autophagy-induced regulation of skeletal muscle mass and cellular quality control.
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Interleucina-15 , Músculo Esquelético , Camundongos , Masculino , Animais , Interleucina-15/genética , Interleucina-15/metabolismo , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Camundongos Transgênicos , Camundongos Knockout , Proteínas Quinases Ativadas por AMP/metabolismo , AutofagiaRESUMO
Studies in mammals and Drosophila have demonstrated the existence and significance of secreted factors involved in communication between distal organs. In this review, primarily focusing on Drosophila, we examine the known interorgan communication factors and their functions, physiological inducers, and integration in regulating physiology. Moreover, we describe how organ-sensing screens in Drosophila can systematically identify novel conserved interorgan communication factors. Finally, we discuss how interorgan communication enabled and evolved as a result of specialization of organs. Together, we anticipate that future studies will establish a model for metazoan interorgan communication network (ICN) and how it is deregulated in disease.
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Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Adipocinas/metabolismo , Animais , Evolução Biológica , Drosophila/genética , Proteínas de Drosophila/genética , Corpo Adiposo/metabolismo , Mamíferos/metabolismo , Neuropeptídeos/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: High skeletal muscle mass might be a prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC); however, the underlying reason is unclear. We hypothesized that myokines, which are cytokines secreted by the skeletal muscle, function as suppressors of PDAC. We specifically examined irisin, a myokine, which plays a critical role in the modulation of metabolism, to clarify the anticancer mechanisms. METHODS: First, the effect of the conditioned medium (CM) from skeletal muscle cells and from irisin-knockdown skeletal muscle cells on PDAC cell lines was evaluated. We then investigated the effects and anticancer mechanism of irisin in PDAC cells, and evaluated the anticancer effect of recombinant irisin in a PDAC xenograft mouse model. Finally, patients undergoing pancreatic resection for PDAC were divided into two groups based on their serum irisin level, and the long-term outcomes were evaluated. RESULTS: The CM enhanced gemcitabine sensitivity by inducing apoptosis and decreasing cell migration by inhibiting epithelial-mesenchymal transition (EMT) in PDAC cell lines. The CM derived from irisin-knockdown skeletal muscle cells did not affect the PDAC cell lines. The addition of recombinant irisin to PDAC cell lines facilitated sensitivity to gemcitabine by inhibiting the mitogen-activated protein kinase (MAPK) pathway, and decreased migration by inhibiting EMT via the transforming growth factor-ß/SMAD pathway. Xenografts injected with gemcitabine and recombinant irisin grew slower than the xenografts injected with gemcitabine alone. The overall survival was prolonged in the high-irisin group compared with that in the low-irisin group. CONCLUSIONS: Skeletal muscle-derived irisin may affect PDAC by enhancing its sensitivity to gemcitabine and suppressing EMT.
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Antimetabólitos Antineoplásicos , Apoptose , Carcinoma Ductal Pancreático , Movimento Celular , Proliferação de Células , Desoxicitidina , Transição Epitelial-Mesenquimal , Fibronectinas , Gencitabina , Músculo Esquelético , Neoplasias Pancreáticas , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Feminino , Humanos , Masculino , Camundongos , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fibronectinas/metabolismo , Fibronectinas/farmacologia , Camundongos Nus , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , IdosoRESUMO
Myokines are a group of cytokines or polypeptides released from skeletal muscle during exercise. Growing evidence suggests that myokines are associated with the development of cardiovascular disease (CVD). Moreover, several myokines in peripheral blood exhibit dynamic changes in different CVD stages. This review summarizes the potential roles of myokines such as myostatin, irisin, brain-derived neurotrophic factor, mitsugumin 53, meteorin-like, and apelin in various CVD, including myocardial infarction, heart failure, atherosclerosis, hypertension, and diabetes. The association of these myokines with biomarkers currently being used in clinical practice is also discussed. Furthermore, the review considers the emerging role of myokines in CVD and addresses the challenges remaining in translating these discoveries into novel clinical biomarkers for CVD.
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Hair loss affects men and women of all ages. Myokines, which are mainly secreted by skeletal muscles during exercise, have numerous health benefits. VEGF, IGF-1, FGF and irisin are reprehensive myokines. Although VEGF, IGF-1 and FGF are positively associated with hair growth, few studies have researched the effects of irisin on hair growth. Here, we investigated whether irisin promotes hair growth using in vitro, ex vivo and in vivo patch assays, as well as mouse models. We show that irisin increases proliferation, alkaline phosphatase (ALP) activity and mitochondrial membrane potential in human dermal papilla cells (hDPCs). Irisin activated the Wnt/ß-catenin signalling pathway, thereby upregulating Wnt5a, Wnt10b and LEF-1, which play an important role in hair growth. Moreover, irisin enhanced human hair shaft elongation. In vivo, patch assays revealed that irisin promotes the generation of new hair follicles, accelerates entry into the anagen phase, and significantly increases hair growth in C57BL/6 mice. However, XAV939, a Wnt/ß-catenin signalling inhibitor, suppressed the irisin-mediated increase in hair shaft and hair growth. These results indicate that irisin increases hair growth via the Wnt/ß-catenin pathway and highlight its therapeutic potential in hair loss treatment.
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Fibronectinas , Glicogênio Sintase Quinase 3 beta , Folículo Piloso , Cabelo , Camundongos Endogâmicos C57BL , Via de Sinalização Wnt , beta Catenina , Animais , Humanos , Fibronectinas/metabolismo , Camundongos , Glicogênio Sintase Quinase 3 beta/metabolismo , Cabelo/crescimento & desenvolvimento , beta Catenina/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Proliferação de Células , Proteína Wnt-5a/metabolismo , Proteínas Wnt/metabolismo , Masculino , Feminino , Proteínas Proto-OncogênicasRESUMO
A new target that stimulates bone formation is needed to overcome limitations of current anti-osteoporotic drugs. Myokines, factors secreted from muscles, may modulate it. In this study, we investigated the role of aortic carboxypeptidase-like protein (ACLP), which is highly expressed in skeletal muscles, on bone formation. MC3T3-E1 cells and/or calvaria osteoblasts were treated with recombinant N-terminal mouse ACLP containing a signal peptide [rmACLP (N)]. The expression and secretion of ACLP were higher in skeletal muscle and differentiated myotube than in other tissues and undifferentiated myoblasts, respectively. rmACLP (N) increased bone formation, ALP activity, and phosphorylated p38 mitogen-activated protein (MAP) kinase in osteoblasts; reversal was achieved by pre-treatment with a TGF-ß receptor inhibitor. Under H2 O2 treatment, rmACLP (N) increased osteoblast survival, phosphorylated p38 MAP kinase, and the nuclear translocation of FoxO3a in osteoblasts. H2 O2 treatment caused rmACLP (N) to suppress its apoptotic, oxidative, and caspase-9 activities. rmACLP (N)-stimulated osteoblast survival was reversed by pre-treatment with a p38 inhibitor, a TGF-ß-receptor II blocking antibody, and a FoxO3a shRNA. Conditioned media (CM) from muscle cells stimulated osteoblast survival under H2 O2 treatment, in contrast to CM from ACLP knockdown muscle cells. rmACLP (N) increased the expressions of FoxO3a target anti-oxidant genes such as Sod2, Trx2, and Prx5. In conclusion, ACLP stimulated the differentiation and survival of osteoblasts. This led to the stimulation of bone formation by the activation of p38 MAP kinase and/or FoxO3a via TGF-ß receptors. These findings suggest a novel role for ACLP in bone metabolism as a putative myokine.
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Carboxipeptidases , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Camundongos , Diferenciação Celular/fisiologia , Carboxipeptidases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Osteogênese , Osteoblastos/metabolismo , FosforilaçãoRESUMO
INTRODUCTION: Individuals with spinal cord injury (SCI) can experience accelerated cognitive aging. Myokines (factors released from muscle cells during contractions), such as brain-derived neurotrophic factor (BDNF), are thought to have beneficial effects on cognition. Neuromuscular electrical stimulation (NMES) was shown to elicit a large release of myokines. However, the effects of NMES on cognitive function have not been studied. OBJECTIVE: To present the study protocol for a clinical trial evaluating the effects of NMES aimed at improving cognition and BDNF. METHODS: A replicated randomized three-phases single-case experimental design (SCED) with sequential multiple baseline time series and a single-armed prospective trial will be conducted with 15 adults with chronic SCI (> 12 months after injury) above L1 neurological level undergoing 30-min quadriceps NMES, 3 days per week for 12 weeks. MAIN STUDY ENDPOINTS: Primary endpoint is cognitive performance (assessed by a smartphone test) conducted three times per week during the baseline phase with random duration of 3 to 8 weeks, the intervention phase of 12 weeks, and the follow-up phase of 3 weeks after a no measurement rest period of 12 weeks. Secondary endpoints are changes in BDNF levels and cognitive performance measured before the baseline period, before and after intervention and after a 12 weeks follow-up. CONCLUSION: This will be the first study investigating the effects of 12 weeks NMES on both cognition and BDNF levels in individuals with SCI. The SCED results provide information on individual treatment effect courses which may direct future research. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05822297, 12/01/2023).
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Fator Neurotrófico Derivado do Encéfalo , Terapia por Estimulação Elétrica , Traumatismos da Medula Espinal , Humanos , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/psicologia , Traumatismos da Medula Espinal/reabilitação , Terapia por Estimulação Elétrica/métodos , Adulto , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Feminino , Estudos de Caso Único como Assunto , Cognição/fisiologia , Pessoa de Meia-Idade , Projetos de PesquisaRESUMO
INTRODUCTION: This study aimed to investigate the prospective role of serum irisin - a novel adipo-myokine - in all-cause mortality and cardiovascular (CV) mortality in patients on peritoneal dialysis (PD). METHODS: A prospectively observational study was conducted with 154 PD patients. Baseline clinical data were collected from the medical records. Serum irisin concentrations were determined using enzyme-linked immunosorbent assay. Patients were divided into the high irisin group (serum irisin ≥113.5 ng/mL) and the low irisin group (serum irisin <113.5 ng/mL) based on the median value of serum irisin. A body composition monitor was used to monitor body composition. Cox regression analysis was utilized to find the independent risk factors of all-cause and CV mortality in PD patients. RESULTS: The median serum irisin concentration was 113.5 ng/mL (interquartile range, 106.2-119.8 ng/mL). Patients in the high irisin group had significantly higher muscle mass and carbon dioxide combining power (CO2CP) than those in the low irisin group (p < 0.05). Serum irisin was positively correlated with pulse pressure, CO2CP, and muscle mass, while negatively correlated with body fat percentage (p < 0.05). During a median of follow-up for 60.0 months, there were 55 all-cause deaths and 26 CV deaths. Patients in the high irisin group demonstrated a higher CV survival rate than those in the low irisin group (p = 0.016). Multivariate Cox regression analysis showed that high irisin level (hazard ratio [HR], 0.341; 95% confidence interval [CI], 0.135-0.858; p = 0.022), age, and diabetic mellitus were independently associated with CV mortality in PD patients. However, serum irisin level failed to demonstrate a statistically significant relationship with all-cause mortality. CONCLUSION: Low serum irisin levels at baseline were independently predictive of CV mortality but not all-cause mortality in PD patients. Therefore, serum irisin could be a potential target for monitoring CV outcomes in PD patients.
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Doenças Cardiovasculares , Diálise Peritoneal , Humanos , Fibronectinas , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
Skeletal muscles serve both in movement and as endocrine organs. Myokines secreted by skeletal muscles activate biological functions within muscles and throughout the body via autocrine, paracrine, and/or endocrine pathways. Skeletal muscle atrophy can influence myokine expression and secretion, while myokines can impact the structure and function of skeletal muscles. Regulating the expression and secretion of myokines through the pharmacological approach is a strategy for alleviating skeletal muscle atrophy. Natural products possess complex structures and chemical properties. Previous studies have demonstrated that various natural products exert beneficial effects on skeletal muscle atrophy. This article reviewed the regulatory effects of natural products on myokines and summarized the research progress on skeletal muscle atrophy associated with myokine regulation. The focus is on how small-molecule natural products affect the regulation of interleukin 6 (IL-6), irisin, myostatin, IGF-1, and FGF-21 expression. We contend that the development of small-molecule natural products targeting the regulation of myokines holds promise in combating skeletal muscle atrophy.
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Produtos Biológicos , Músculo Esquelético , Atrofia Muscular , Atrofia Muscular/metabolismo , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/patologia , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Humanos , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Miostatina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-6/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , MiocinasRESUMO
Skeletal muscle (SKM), despite comprising ~40% of body mass, rarely manifests cancer. This review explores the mechanisms that help to explain this rarity, including unique SKM architecture and function, which prohibits the development of new cancer as well as negates potential metastasis to SKM. SKM also presents a unique immune environment that may magnify the anti-tumorigenic effect. Moreover, the SKM microenvironment manifests characteristics such as decreased extracellular matrix stiffness and altered lactic acid, pH, and oxygen levels that may interfere with tumor development. SKM also secretes anti-tumorigenic myokines and other molecules. Collectively, these mechanisms help account for the rarity of SKM cancer.
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Neoplasias Musculares , Músculo Esquelético , Microambiente Tumoral , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Microambiente Tumoral/imunologia , Neoplasias Musculares/metabolismo , Neoplasias Musculares/patologia , AnimaisRESUMO
This study aimed to investigate the effects of a single bench press (BP) vs. leg press (LP) resistance training sessions on testosterone, cortisol, C-reactive protein (CRP) interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) concentrations, and creatine kinase (CK) activity in strength-trained males. Eleven strength-trained males participated in a cross-over randomized trial, undergoing two experimental sessions each consisting of five sets of the BP or the LP exercise to volitional failure with a load corresponding to 50% of one-repetition maximum. Blood samples were taken at baseline (BA), immediately post (POST), and 1 h after the cessation of exercise (POST-1). A significant increase in IL-6 concentration from BA to POST-1 was observed during the LP condition (p = 0.004; effect size [ES] = 0.64). Additionally, a significant main effect of time was found for increasing testosterone concentrations from BA to POST exercise (p = 0.014; ES = 0.25). A significantly lower cortisol concentration at POST-1 compared to POST (p = 0.001; ES = 1.02) was noted in the BP condition. Furthermore, a significantly lower cortisol concentration was found at POST-1 in the BP compared to the LP condition (p = 0.022; ES = 1.3). A significant increase in CK activity was reported from BA to POST (p = 0.024; ES = 0.69) and POST-1 (p = 0.045; ES = 0.55) during the LP condition, and from BA to POST-1 (p = 0.014; ES = 0.96) during the BP condition. No significant differences were found in the CRP (p = 0.659) and TNF-α concentrations (p = 0.487). These results suggest that the amount of muscle mass engaged during the resistance exercise may influence the changes in IL-6 and cortisol concentrations. Larger muscle groups, as engaged in the LP, more likely lead to elevated concentrations of IL-6 myokine.
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Hidrocortisona , Interleucina-6 , Treinamento Resistido , Testosterona , Fator de Necrose Tumoral alfa , Humanos , Masculino , Hidrocortisona/sangue , Testosterona/sangue , Adulto , Fator de Necrose Tumoral alfa/sangue , Interleucina-6/sangue , Proteína C-Reativa/metabolismo , Adulto Jovem , Creatina Quinase/sangue , Inflamação/sangue , Estudos Cross-OverRESUMO
Background/objectives: Exercise intensity is potentially an important regulator of various exerkines secretion, but the optimal exercise intensity to increase and sustain exerkines levels, including FGF-21, FSTL-1, cathepsin B, and BDNF in humans, has not yet been fully elucidated. This study aimed to examine the circulating levels of FGF-21, FSTL-1, cathepsin B, and BDNF according to the exercise intensity. Methods: Nine young men (24.0 ± 0.4 years old) performed 4 different experimental sessions at 1-week intervals: 1) a control session (CTRL; no exercise); 2) moderate-intensity continuous exercise (MICE, 55% HRR); 3) vigorous-intensity continuous exercise (VICE, 85% HRR); and 4) high-intensity interval exercise (HIIE, 4 repetitions of a 30-s of "all out" cycling workout followed by a 4-min recovery). Blood samples were collected at 4 different time points (pre-exercise, immediately post-exercise, 30 min post-exercise, and 90 min post-exercise). Results: Serum FGF-21, FSTL-1, cathepsin B, and BDNF were higher in HIIE than in CTRL immediately post-exercise, and FSTL-1, cathepsin B, and BDNF were higher in HIIE than in MICE immediately post-exercise (P < 0.05). The AUC for FGF-21, FSTL-1, and BDNF was higher in HIIE than in CTRL, and the AUC for FGF-21 and BDNF was higher in HIIE than in MICE (P < 0.05). Furthermore, the change in blood lactate was positively correlated with the changes in all exerkines. Conclusions: This study demonstrates that acute HIIE effectively increases serum FGF-21, FSTL-1, cathepsin B, and BDNF compared to MICE. Therefore, the secretion of exerkines, including FGF-21, FSTL-1, cathepsin B, and BDNF may be exercise intensity-dependent.
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Acute exercise induces changes in circulating proteins, which are known to alter metabolism and systemic energy balance. Skeletal muscle is a primary contributor to changes in the plasma proteome with acute exercise. An important consideration when assessing the endocrine function of muscle is the presence of different fiber types, which show distinct functional and metabolic properties and likely secrete different proteins. Similarly, adipokines are important regulators of systemic metabolism and have been shown to differ between depots. Given the health-promoting effects of exercise, we proposed that understanding depot-specific remodeling of protein secretion in muscle and adipose tissue would provide new insights into intertissue communication and uncover novel regulators of energy homeostasis. Here, we examined the effect of endurance exercise training on protein secretion from fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscle and visceral and subcutaneous adipose tissue. High-fat diet-fed mice were exercise trained for 6 wk, whereas a Control group remained sedentary. Secreted proteins from excised EDL and soleus muscle, inguinal, and epididymal adipose tissues were detected using mass spectrometry. We detected 575 and 784 secreted proteins from EDL and soleus muscle and 738 and 920 proteins from inguinal and epididymal adipose tissue, respectively. Of these, 331 proteins were secreted from all tissues, whereas secretion of many other proteins was tissue and depot specific. Exercise training led to substantial remodeling of protein secretion from EDL, whereas soleus showed only minor changes. Myokines released exclusively from EDL or soleus were associated with glycogen metabolism and cellular stress response, respectively. Adipokine secretion was completely refractory to exercise regulation in both adipose depots. This study provides an in-depth resource of protein secretion from muscle and adipose tissue, and its regulation following exercise training, and identifies distinct depot-specific secretion patterns that are related to the metabolic properties of the tissue of origin.NEW & NOTEWORTHY The present study examines the effects of exercise training on protein secretion from fast-twitch and slow-twitch muscle as well as visceral and subcutaneous adipose tissue of obese mice. Although exercise training leads to substantial remodeling of protein secretion from fast-twitch muscle, adipose tissue is completely refractory to exercise regulation.
Assuntos
Músculo Esquelético , Condicionamento Físico Animal , Masculino , Camundongos , Animais , Camundongos Obesos , Músculo Esquelético/metabolismo , Tecido Adiposo/metabolismo , Obesidade/terapia , Obesidade/metabolismo , Condicionamento Físico Animal/fisiologia , Adipocinas/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Fibras Musculares de Contração Rápida/metabolismoRESUMO
Muscle contractile activity stimulates intramuscular recruitment of immune cells including neutrophils emerging to serve as a prerequisite for exerting proper muscular performance, although the underlying mechanisms and their contributions to myokine upregulation remain ill-defined. We previously reported that pharmacological inhibition of CX3CR1, a fractalkine receptor, dampens gnawing-dependent neutrophil recruitment into masseter muscles along with compromising their masticatory activity. By using a running exercise model, we herein demonstrated that hindlimb muscles require collaborative actions of both CX3CR1- and CXCR2-mediated signals for achieving neutrophil recruitment, upregulation of myokines including interleukin (IL)-6, enhanced GLUT4 translocation, and adequate endurance capability. Mechanistically, we revealed that a combination of CX3CR1 and CXCR2 antagonists, i.e., AZD8797 and SB2205002, inhibits exercise-inducible ICAM-1 and fractalkine upregulations in the area of the endothelium and muscle-derived CXCL1 upregulation, both of which apparently contribute to the intramuscular neutrophil accumulation in working muscles. Intriguingly, we also observed that 2 h of running results in intramuscular augmentation of innate lymphoid type 2 cells (ILC2s) markers, i.e., Bcl11b mRNA levels and anti-GATA-3-antibody-positive signals, and that these effects are completely abolished by administration of the combination of CX3CR1 and CXCR2 antagonists. Taken together, our findings strongly suggest that the exercise-evoked regional interplay among working myofibers, the adjacent endothelium, and recruited immune cells including neutrophils and possibly ILC2s, mediated through these local factors, plays a key role in the organization of the intramuscular microenvironment supporting the performance of hindlimb muscles during running.NEW & NOTEWORTHY This study provides compelling evidence that running-dependent intramuscular neutrophil recruitment requires both CX3CR1- and CXCR2-mediated signals that prime not only myofiber-derived myokine upregulations but also endothelium ICAM-1 and fractalkine expressions. The results revealed the importance of the exercise-evoked regional interplay among working myofibers, the adjacent endothelium, and recruited immune cells, including neutrophils and possibly ILC2s, which plays a key role in the organization of the intramuscular microenvironment supporting the performance of hindlimb muscles during running.
Assuntos
Imunidade Inata , Corrida , Animais , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão Intercelular/farmacologia , Interleucina-6/metabolismo , Linfócitos , Infiltração de Neutrófilos , Neutrófilos , Regulação para Cima , Receptores de Interleucina-8B/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismoRESUMO
Physical exercise may improve cognitive function by modulating molecular and cellular mechanisms within the brain. We propose that the facilitation of long-term synaptic potentiation (LTP)-related pathways, by products induced by physical exercise (i.e., exerkines), is a crucial aspect of the exercise-effect on the brain. This review summarizes synaptic pathways that are activated by exerkines and may potentiate LTP. For a total of 16 exerkines, we indicated how blood and brain exerkine levels are altered depending on the type of physical exercise (i.e., cardiovascular or resistance exercise) and how they respond to a single bout (i.e., acute exercise) or multiple bouts of physical exercise (i.e., chronic exercise). This information may be used for designing individualized physical exercise programs. Finally, this review may serve to direct future research towards fundamental gaps in our current knowledge regarding the biophysical interactions between muscle activity and the brain at both cellular and system levels.