RESUMEN
Entry of enveloped viruses into cells is mediated by viral fusogenic proteins that drive membrane rearrangements needed for fusion between viral and target membranes. Skeletal muscle development also requires membrane fusion events between progenitor cells to form multinucleated myofibers. Myomaker and Myomerger are muscle-specific cell fusogens but do not structurally or functionally resemble classical viral fusogens. We asked whether the muscle fusogens could functionally substitute for viral fusogens, despite their structural distinctiveness, and fuse viruses to cells. We report that engineering of Myomaker and Myomerger on the membrane of enveloped viruses leads to specific transduction of skeletal muscle. We also demonstrate that locally and systemically injected virions pseudotyped with the muscle fusogens can deliver µDystrophin to skeletal muscle of a mouse model of Duchenne muscular dystrophy and alleviate pathology. Through harnessing the intrinsic properties of myogenic membranes, we establish a platform for delivery of therapeutic material to skeletal muscle.
Asunto(s)
Bioingeniería , Lentivirus , Proteínas de la Membrana , Músculo Esquelético , Distrofia Muscular de Duchenne , Animales , Ratones , Fusión Celular , Fusión de Membrana , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Desarrollo de Músculos , Músculo Esquelético/metabolismo , Músculo Esquelético/virología , Bioingeniería/métodos , Distrofia Muscular de Duchenne/terapia , Modelos Animales de Enfermedad , Tropismo Viral , Lentivirus/genéticaRESUMEN
Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.
Asunto(s)
Caquexia , Humanos , Caquexia/tratamiento farmacológico , Caquexia/etiología , Caquexia/metabolismo , Caquexia/patología , Músculo Esquelético/metabolismo , Neoplasias/complicaciones , Neoplasias/metabolismo , Neoplasias/patología , Infecciones/complicaciones , Infecciones/patología , Insuficiencia Multiorgánica/complicaciones , Insuficiencia Multiorgánica/patologíaRESUMEN
Skeletal muscle size is highly plastic and sensitive to a variety of stimuli. Muscle atrophy occurs as the result of changes in multiple signaling pathways that regulate both protein synthesis and degradation. The signaling pathways that are activated or inhibited depend on the specific stimuli that are altered. To view this SnapShot, open of download the PDF.
Asunto(s)
Músculo Esquelético , Atrofia Muscular , Humanos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Transducción de Señal/fisiologíaRESUMEN
Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health and disease. Here, we determine the molecular architecture of native vertebrate skeletal sarcomeres by electron cryo-tomography. Our reconstruction reveals molecular details of the three-dimensional organization and interaction of actin and myosin in the A-band, I-band, and Z-disc and demonstrates that α-actinin cross-links antiparallel actin filaments by forming doublets with 6-nm spacing. Structures of myosin, tropomyosin, and actin at ~10 Å further reveal two conformations of the "double-head" myosin, where the flexible orientation of the lever arm and light chains enable myosin not only to interact with the same actin filament, but also to split between two actin filaments. Our results provide unexpected insights into the fundamental organization of vertebrate skeletal muscle and serve as a strong foundation for future investigations of muscle diseases.
Asunto(s)
Músculo Esquelético/metabolismo , Sarcómeros/química , Citoesqueleto de Actina/química , Citoesqueleto de Actina/metabolismo , Actinina/química , Actinina/metabolismo , Actomiosina/química , Actomiosina/metabolismo , Animales , Microscopía por Crioelectrón , Femenino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Unión Proteica , Sarcómeros/metabolismo , Sarcómeros/ultraestructura , Tropomiosina/química , Tropomiosina/metabolismoRESUMEN
Replacing or editing disease-causing mutations holds great promise for treating many human diseases. Yet, delivering therapeutic genetic modifiers to specific cells in vivo has been challenging, particularly in large, anatomically distributed tissues such as skeletal muscle. Here, we establish an in vivo strategy to evolve and stringently select capsid variants of adeno-associated viruses (AAVs) that enable potent delivery to desired tissues. Using this method, we identify a class of RGD motif-containing capsids that transduces muscle with superior efficiency and selectivity after intravenous injection in mice and non-human primates. We demonstrate substantially enhanced potency and therapeutic efficacy of these engineered vectors compared to naturally occurring AAV capsids in two mouse models of genetic muscle disease. The top capsid variants from our selection approach show conserved potency for delivery across a variety of inbred mouse strains, and in cynomolgus macaques and human primary myotubes, with transduction dependent on target cell expressed integrin heterodimers.
Asunto(s)
Cápside/metabolismo , Dependovirus/metabolismo , Evolución Molecular Dirigida , Técnicas de Transferencia de Gen , Músculo Esquelético/metabolismo , Secuencia de Aminoácidos , Animales , Cápside/química , Células Cultivadas , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Integrinas/metabolismo , Macaca fascicularis , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Duchenne/terapia , Miopatías Estructurales Congénitas/patología , Miopatías Estructurales Congénitas/terapia , Multimerización de Proteína , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/uso terapéutico , ARN Guía de Kinetoplastida/metabolismo , Recombinación Genética/genética , Especificidad de la Especie , TransgenesRESUMEN
Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.
Asunto(s)
Epigénesis Genética , Ejercicio Físico , Ejercicio Físico/fisiología , Adaptación Fisiológica/fisiología , Mitocondrias/metabolismo , Músculo Esquelético/metabolismoRESUMEN
In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.
Asunto(s)
Músculo Esquelético/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Ácido Succínico/metabolismo , Animales , Humanos , Concentración de Iones de Hidrógeno , Inflamación/metabolismo , Ratones , Mitocondrias/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Contracción Muscular , Receptores Acoplados a Proteínas G/fisiología , Transducción de Señal , Succinatos/metabolismo , Simportadores/metabolismoRESUMEN
Muscle spasticity after nervous system injuries and painful low back spasm affect more than 10% of global population. Current medications are of limited efficacy and cause neurological and cardiovascular side effects because they target upstream regulators of muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation; however, targeting skeletal myosin is particularly challenging because of its similarity to the cardiac isoform. We identified a key residue difference between these myosin isoforms, located in the communication center of the functional regions, which allowed us to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structure of MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targeting skeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems, without cardiovascular side effects and improved spastic gait disorders after brain injury in a disease model. MPH-220 provides a potential nervous-system-independent option to treat spasticity and muscle stiffness.
Asunto(s)
Músculo Esquelético/metabolismo , Miosinas del Músculo Esquelético/efectos de los fármacos , Miosinas del Músculo Esquelético/genética , Adulto , Animales , Miosinas Cardíacas/genética , Miosinas Cardíacas/metabolismo , Línea Celular , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Masculino , Ratones , Contracción Muscular/fisiología , Fibras Musculares Esqueléticas/fisiología , Espasticidad Muscular/genética , Espasticidad Muscular/fisiopatología , Músculo Esquelético/fisiología , Miosinas/efectos de los fármacos , Miosinas/genética , Miosinas/metabolismo , Isoformas de Proteínas , Ratas , Ratas Wistar , Miosinas del Músculo Esquelético/metabolismoRESUMEN
Skeletal muscle contains a designated population of adult stem cells, called satellite cells, which are generally quiescent. In homeostasis, satellite cells proliferate only sporadically and usually by asymmetric cell division to replace myofibres damaged by daily activity and maintain the stem cell pool. However, satellite cells can also be robustly activated upon tissue injury, after which they undergo symmetric divisions to generate new stem cells and numerous proliferating myoblasts that later differentiate to muscle cells (myocytes) to rebuild the muscle fibre, thereby supporting skeletal muscle regeneration. Recent discoveries show that satellite cells have a great degree of population heterogeneity, and that their cell fate choices during the regeneration process are dictated by both intrinsic and extrinsic mechanisms. Extrinsic cues come largely from communication with the numerous distinct stromal cell types in their niche, creating a dynamically interactive microenvironment. This Review discusses the role and regulation of satellite cells in skeletal muscle homeostasis and regeneration. In particular, we highlight the cell-intrinsic control of quiescence versus activation, the importance of satellite cell-niche communication, and deregulation of these mechanisms associated with ageing. The increasing understanding of how satellite cells are regulated will help to advance muscle regeneration and rejuvenation therapies.
Asunto(s)
Células Satélite del Músculo Esquelético , Diferenciación Celular/fisiología , Músculo Esquelético/metabolismo , Células Satélite del Músculo Esquelético/fisiología , Células MadreRESUMEN
Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue - encompassing the muscle cells (myofibres) themselves and their extracellular matrix - or muscle fibre innervation. Since the identification in 1987 of the first genetic lesion associated with a neuromuscular disorder - mutations in dystrophin as an underlying cause of Duchenne muscular dystrophy - the field has made tremendous progress in understanding the genetic basis of these diseases, with pathogenic variants in more than 500 genes now identified as underlying causes of neuromuscular disorders. The subset of neuromuscular disorders that affect skeletal muscle are referred to as myopathies or muscular dystrophies, and are due to variants in genes encoding muscle proteins. Many of these proteins provide structural stability to the myofibres or function in regulating sarcolemmal integrity, whereas others are involved in protein turnover, intracellular trafficking, calcium handling and electrical excitability - processes that ensure myofibre resistance to stress and their primary activity in muscle contraction. In this Review, we discuss how defects in muscle proteins give rise to muscle dysfunction, and ultimately to disease, with a focus on pathologies that are most common, best understood and that provide the most insight into muscle biology.
Asunto(s)
Distrofina/genética , Proteínas Musculares/genética , Distrofia Muscular de Duchenne/genética , Enfermedades Neuromusculares/genética , Humanos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/patología , Mutación/genética , Enfermedades Neuromusculares/patologíaRESUMEN
Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues - prominently in muscle, fat and liver - is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia and hyperlipidaemia. Insulin resistance is caused by a combination of genetic and environmental factors. Recent genetic and biochemical studies suggest a key role for adipose tissue in the development of insulin resistance, potentially by releasing lipids and other circulating factors that promote insulin resistance in other organs. These extracellular factors perturb the intracellular concentration of a range of intermediates, including ceramide and other lipids, leading to defects in responsiveness of cells to insulin. Such intermediates may cause insulin resistance by inhibiting one or more of the proximal components in the signalling cascade downstream of insulin (insulin receptor, insulin receptor substrate (IRS) proteins or AKT). However, there is now evidence to support the view that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway that is more closely linked to the terminal biological response. Identifying these targets is of major importance, as it will reveal potential new targets for treatments of diseases associated with insulin resistance.
Asunto(s)
Antígenos CD/genética , Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Insulina/genética , Receptor de Insulina/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Glucosa/genética , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Hígado/metabolismo , Hígado/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/genéticaRESUMEN
Metabolic diseases are often characterized by circadian misalignment in different tissues, yet how altered coordination and communication among tissue clocks relate to specific pathogenic mechanisms remains largely unknown. Applying an integrated systems biology approach, we performed 24-hr metabolomics profiling of eight mouse tissues simultaneously. We present a temporal and spatial atlas of circadian metabolism in the context of systemic energy balance and under chronic nutrient stress (high-fat diet [HFD]). Comparative analysis reveals how the repertoires of tissue metabolism are linked and gated to specific temporal windows and how this highly specialized communication and coherence among tissue clocks is rewired by nutrient challenge. Overall, we illustrate how dynamic metabolic relationships can be reconstructed across time and space and how integration of circadian metabolomics data from multiple tissues can improve our understanding of health and disease.
Asunto(s)
Relojes Circadianos/fisiología , Metaboloma , Animales , Dieta Alta en Grasa , Metabolismo Energético , Hígado/metabolismo , Masculino , Redes y Vías Metabólicas , Metabolómica , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Corteza Prefrontal/metabolismo , Núcleo Supraquiasmático/metabolismo , Proteína Desacopladora 1/metabolismoRESUMEN
A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.
Asunto(s)
Envejecimiento , Sulfuro de Hidrógeno/metabolismo , NAD/metabolismo , Animales , Células Endoteliales/citología , Células Endoteliales/metabolismo , Humanos , Ratones , Ratones Noqueados , Microvasos/metabolismo , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Neovascularización Fisiológica , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Condicionamiento Físico Animal , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genética , Sirtuina 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Injured skeletal muscle regenerates, but with age or in muscular dystrophies, muscle is replaced by fat. Upon injury, muscle-resident fibro/adipogenic progenitors (FAPs) proliferated and gave rise to adipocytes. These FAPs dynamically produced primary cilia, structures that transduce intercellular cues such as Hedgehog (Hh) signals. Genetically removing cilia from FAPs inhibited intramuscular adipogenesis, both after injury and in a mouse model of Duchenne muscular dystrophy. Blocking FAP ciliation also enhanced myofiber regeneration after injury and reduced myofiber size decline in the muscular dystrophy model. Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes, pointing to a strategy to combat fatty degeneration of skeletal muscle. We conclude that ciliary Hh signaling by FAPs orchestrates the regenerative response to skeletal muscle injury.
Asunto(s)
Adipogénesis , Proteínas Hedgehog/metabolismo , Músculo Esquelético/metabolismo , Transducción de Señal , Células Madre/metabolismo , Adipocitos/metabolismo , Animales , Cilios/metabolismo , Distrofina/genética , Metaloproteinasa 14 de la Matriz/metabolismo , Ratones , Desarrollo de Músculos , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Regeneración , Inhibidor Tisular de Metaloproteinasa-3/metabolismoRESUMEN
MiRNAs are regulatory molecules that can be packaged into exosomes and secreted from cells. Here, we show that adipose tissue macrophages (ATMs) in obese mice secrete miRNA-containing exosomes (Exos), which cause glucose intolerance and insulin resistance when administered to lean mice. Conversely, ATM Exos obtained from lean mice improve glucose tolerance and insulin sensitivity when administered to obese recipients. miR-155 is one of the miRNAs overexpressed in obese ATM Exos, and earlier studies have shown that PPARγ is a miR-155 target. Our results show that miR-155KO animals are insulin sensitive and glucose tolerant compared to controls. Furthermore, transplantation of WT bone marrow into miR-155KO mice mitigated this phenotype. Taken together, these studies show that ATMs secrete exosomes containing miRNA cargo. These miRNAs can be transferred to insulin target cell types through mechanisms of paracrine or endocrine regulation with robust effects on cellular insulin action, in vivo insulin sensitivity, and overall glucose homeostasis.
Asunto(s)
Tejido Adiposo/citología , Resistencia a la Insulina , Macrófagos/metabolismo , MicroARNs/metabolismo , Adipocitos/metabolismo , Animales , Células Cultivadas , Glucosa/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células Musculares/metabolismo , Músculo Esquelético/metabolismo , Transducción de SeñalRESUMEN
PGC-1α is well established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1α activates gene transcription are incompletely understood. Here, we report that PGC-1α serves as a scaffold protein that physically and functionally connects the DNA-binding protein estrogen-related receptor α (ERRα), cap-binding protein 80 (CBP80), and Mediator to overcome promoter-proximal pausing of RNAPII and transcriptionally activate stress-response genes. We show that PGC-1α promotes pausing release in a two-arm mechanism (1) by recruiting the positive transcription elongation factor b (P-TEFb) and (2) by outcompeting the premature transcription termination complex Integrator. Using mice homozygous for five amino acid changes in the CBP80-binding motif (CBM) of PGC-1α that destroy CBM function, we show that efficient differentiation of primary myoblasts to myofibers and timely skeletal muscle regeneration after injury require PGC-1α binding to CBP80. Our findings reveal how PGC-1α activates stress-response gene transcription in a previously unanticipated pre-mRNA quality-control pathway.
Asunto(s)
Precursores del ARN , Factores de Transcripción , Animales , Ratones , Proteínas de Unión al ADN/genética , Músculo Esquelético/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Regiones Promotoras Genéticas , Proteínas de Unión a Caperuzas de ARN/genética , ARN Polimerasa II/metabolismo , Precursores del ARN/metabolismo , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
Repeated, episodic bouts of skeletal muscle contraction undertaken frequently as structured exercise training are a potent stimulus for physiological adaptation in many organs. Specifically, in skeletal muscle, remarkable plasticity is demonstrated by the remodeling of muscle structure and function in terms of muscular size, force, endurance, and contractile velocity as a result of the functional demands induced by various types of exercise training. This plasticity, and the mechanistic basis for adaptations to skeletal muscle in response to exercise training, are underpinned by activation and/or repression of molecular pathways and processes in response to each individual acute exercise session. These pathways include the transduction of signals arising from neuronal, mechanical, metabolic, and hormonal stimuli through complex signal transduction networks, which are linked to a myriad of effector proteins involved in the regulation of pre- and posttranscriptional processes, and protein translation and degradation processes. This review therefore describes acute exercise-induced signal transduction and the molecular responses to acute exercise in skeletal muscle including emerging concepts such as epigenetic pre- and posttranscriptional regulation and the regulation of protein translation and degradation. A critical appraisal of methodological approaches and the current state of knowledge informs a series of recommendations offered as future directions in the field.
Asunto(s)
Adaptación Fisiológica , Ejercicio Físico , Humanos , Ejercicio Físico/fisiología , Adaptación Fisiológica/fisiología , Regulación de la Expresión Génica , Aclimatación , Músculo Esquelético/metabolismoRESUMEN
Mechanisms underlying mechanical overload-induced skeletal muscle hypertrophy have been extensively researched since the landmark report by Morpurgo (1897) of "work-induced hypertrophy" in dogs that were treadmill trained. Much of the preclinical rodent and human resistance training research to date supports that involved mechanisms include enhanced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, an expansion in translational capacity through ribosome biogenesis, increased satellite cell abundance and myonuclear accretion, and postexercise elevations in muscle protein synthesis rates. However, several lines of past and emerging evidence suggest that additional mechanisms that feed into or are independent of these processes are also involved. This review first provides a historical account of how mechanistic research into skeletal muscle hypertrophy has progressed. A comprehensive list of mechanisms associated with skeletal muscle hypertrophy is then outlined, and areas of disagreement involving these mechanisms are presented. Finally, future research directions involving many of the discussed mechanisms are proposed.
Asunto(s)
Músculo Esquelético , Transducción de Señal , Humanos , Animales , Perros , Músculo Esquelético/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Biosíntesis de Proteínas , Hipertrofia/metabolismo , Mamíferos/metabolismoRESUMEN
Schieber et al. demonstrate that a specific gut microbiota bacterial strain induces a host-mediated protection mechanism against inflammation-driven wasting syndrome. This salutary effect confers a net survival advantage against bacterial infection, without interfering with the host's pathogen load, revealing that host-microbiota interactions regulate disease tolerance to infection.
Asunto(s)
Escherichia coli/inmunología , Inflamasomas/inmunología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Intestinos/microbiología , Microbiota , Músculo Esquelético/metabolismo , Síndrome Debilitante/inmunología , Síndrome Debilitante/microbiología , AnimalesRESUMEN
To meet the extreme oxygen demand of insect flight muscle, tracheal (respiratory) tubes ramify not only on its surface, as in other tissues, but also within T-tubules and ultimately surrounding every mitochondrion. Although this remarkable physiological specialization has long been recognized, its cellular and molecular basis is unknown. Here, we show that Drosophila tracheoles invade flight muscle T-tubules through transient surface openings. Like other tracheal branching events, invasion requires the Branchless FGF pathway. However, localization of the FGF chemoattractant changes from all muscle membranes to T-tubules as invasion begins. Core regulators of epithelial basolateral membrane identity localize to T-tubules, and knockdown of AP-1γ, required for basolateral trafficking, redirects FGF from T-tubules to surface, increasing tracheal surface ramification and preventing invasion. We propose that tracheal invasion is controlled by an AP-1-dependent switch in FGF trafficking. Thus, subcellular targeting of a chemoattractant can direct outgrowth to specific domains, including inside the cell.