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1.
Cells ; 10(7)2021 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-34359985

RESUMEN

IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, under pathologic conditions, including muscular dystrophy, cancer associated cachexia, aging, chronic inflammatory diseases, and other pathologies, the plasma levels of IL-6 significantly increase, promoting muscle wasting. Nevertheless, the specific physio-pathological role exerted by IL-6 in the maintenance of differentiated phenotype remains to be addressed. The purpose of this study was to define the role of increased plasma levels of IL-6 on muscle homeostasis and the mechanisms contributing to muscle loss. Here, we reported that increased plasma levels of IL-6 promote alteration in muscle growth at early stage of postnatal life and induce muscle wasting by triggering a shift of the slow-twitch fibers toward a more sensitive fast fiber phenotype. These findings unveil a role for IL-6 as a potential biomarker of stunted growth and skeletal muscle wasting.


Asunto(s)
Envejecimiento/patología , Interleucina-6/sangre , Desarrollo de Músculos , Atrofia Muscular/sangre , Síndrome Debilitante/sangre , Animales , Animales Recién Nacidos , Ratones Endogámicos C57BL , Ratones Transgénicos , Fibras Musculares Esqueléticas/patología , Unión Neuromuscular/patología
2.
Antioxidants (Basel) ; 9(10)2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33023202

RESUMEN

Sarcopenia is a progressive age-related loss of skeletal muscle mass and strength, which may result in increased physical frailty and a higher risk of adverse events. Low-grade systemic inflammation, loss of muscle protein homeostasis, mitochondrial dysfunction, and reduced number and function of satellite cells seem to be the key points for the induction of muscle wasting, contributing to the pathophysiological mechanisms of sarcopenia. While a range of genetic, hormonal, and environmental factors has been reported to contribute to the onset of sarcopenia, dietary interventions targeting protein or antioxidant intake may have a positive effect in increasing muscle mass and strength, regulating protein homeostasis, oxidative reaction, and cell autophagy, thus providing a cellular lifespan extension. MicroRNAs (miRNAs) are endogenous small non-coding RNAs, which control gene expression in different tissues. In skeletal muscle, a range of miRNAs, named myomiRNAs, are involved in many physiological processes, such as growth, development, and maintenance of muscle mass and function. This review aims to present and to discuss some of the most relevant molecular mechanisms related to the pathophysiological effect of sarcopenia. Besides, we explored the role of nutrition as a possible way to counteract the loss of muscle mass and function associated with ageing, with special attention paid to nutrient-dependent miRNAs regulation. This review will provide important information to better understand sarcopenia and, thus, to facilitate research and therapeutic strategies to counteract the pathophysiological effect of ageing.

3.
Life Sci Alliance ; 3(10)2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32753528

RESUMEN

RNA-binding proteins orchestrate the composite life of RNA molecules and impact most physiological processes, thus underlying complex phenotypes. The RNA-binding protein Sam68 regulates differentiation processes by modulating splicing, polyadenylation, and stability of select transcripts. Herein, we found that Sam68 -/- mice display altered regulation of alternative splicing in the spinal cord of key target genes involved in synaptic functions. Analysis of the motor units revealed that Sam68 ablation impairs the establishment of neuromuscular junctions and causes progressive loss of motor neurons in the spinal cord. Importantly, alterations of neuromuscular junction morphology and properties in Sam68 -/- mice correlate with defects in muscle and motor unit integrity. Sam68 -/- muscles display defects in postnatal development, with manifest signs of atrophy. Furthermore, fast-twitch muscles in Sam68 -/- mice show structural features typical of slow-twitch muscles, suggesting alterations in the metabolic and functional properties of myofibers. Collectively, our data identify a key role for Sam68 in muscle development and suggest that proper establishment of motor units requires timely expression of synaptic splice variants.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Músculo Esquelético/metabolismo , Unión Neuromuscular/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Empalme Alternativo/genética , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas Motoras/metabolismo , Unión Neuromuscular/fisiología , Empalme del ARN/genética , Empalme del ARN/fisiología , Proteínas de Unión al ARN/genética , Sinapsis/metabolismo
4.
Oxid Med Cell Longev ; 2019: 3018584, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31827671

RESUMEN

The extent of oxidative stress and chronic inflammation are closely related events which coexist in a muscle environment under pathologic conditions. It has been generally accepted that the inflammatory cells, as well as myofibers, are sources of reactive species which are, in turn, able to amplify the activation of proinflammatory pathways. However, the precise mechanism underlining the physiopathologic interplay between ROS generation and inflammatory response has to be fully clarified. Thus, the identification of key molecular players in the interconnected pathogenic network between the two processes might help to design more specific therapeutic approaches for degenerative diseases. Here, we investigated whether elevated circulating levels of the proinflammatory cytokine Interleukin-6 (IL-6) are sufficient to perturb the physiologic redox balance in skeletal muscle, independently of tissue damage and inflammatory response. We observed that the overexpression of circulating IL-6 enhances the generation and accumulation of free radicals in the diaphragm muscle of adult NSE/IL-6 mice, by deregulating redox-associated molecular circuits and impinging the nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated antioxidant response. Our findings are coherent with a model in which uncontrolled levels of IL-6 in the bloodstream can influence the local redox homeostasis, inducing the establishment of prooxidative conditions in skeletal muscle tissue.


Asunto(s)
Interleucina-6/sangre , Músculo Esquelético/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Esquelético/patología , NADPH Oxidasa 2/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Sirtuina 1/metabolismo , Superóxido Dismutasa-1/metabolismo
5.
Curr Genomics ; 20(1): 24-37, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31015789

RESUMEN

The peculiar ability of skeletal muscle tissue to operate adaptive changes during post-natal de-velopment and adulthood has been associated with the existence of adult somatic stem cells. Satellite cells, occupying an exclusive niche within the adult muscle tissue, are considered bona fide stem cells with both stem-like properties and myogenic activities. Indeed, satellite cells retain the capability to both maintain the quiescence in uninjured muscles and to be promptly activated in response to growth or re-generative signals, re-engaging the cell cycle. Activated cells can undergo myogenic differentiation or self-renewal moving back to the quiescent state. Satellite cells behavior and their fate decision are finely controlled by mechanisms involving both cell-autonomous and external stimuli. Alterations in these regu-latory networks profoundly affect muscle homeostasis and the dynamic response to tissue damage, con-tributing to the decline of skeletal muscle that occurs under physio-pathologic conditions. Although the clear myogenic activity of satellite cells has been described and their pivotal role in muscle growth and regeneration has been reported, a comprehensive picture of inter-related mechanisms guiding muscle stem cell activity has still to be defined. Here, we reviewed the main regulatory networks determining satellite cell behavior. In particular, we focused on genetic and epigenetic mechanisms underlining satel-lite cell maintenance and commitment. Besides intrinsic regulations, we reported current evidences about the influence of environmental stimuli, derived from other cell populations within muscle tissue, on satel-lite cell biology.

6.
Mech Ageing Dev ; 170: 37-44, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28851603

RESUMEN

Muscle senescence is a complex mechanism that is usually associated with a decrease in mass, strength and velocity of contraction. This state, known as sarcopenia, is a multifactorial process and it may be the consequence of several events, including accumulation of oxidative stress. The role of oxidative stress in the physiopathology of skeletal muscle is quite complex. Transiently increased levels of oxidative stress might reflect a potentially health promoting process, while an uncontrolled accumulation might have pathological implication. The physiopathological role of oxidative stress on skeletal muscle, its involvement in aging-induced sarcopenia, and potential countermeasures will be discussed.


Asunto(s)
Envejecimiento/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Estrés Oxidativo , Sarcopenia/metabolismo , Sarcopenia/fisiopatología , Envejecimiento/patología , Animales , Humanos , Músculo Esquelético/patología , Sarcopenia/patología
7.
Oxid Med Cell Longev ; 2017: 1987218, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28845212

RESUMEN

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Nevertheless, the mechanisms by which the absence of dystrophin leads to muscle degeneration remain to be fully elucidated. An imbalance between oxidant and antioxidant systems has been proposed as a secondary effect of DMD. However, the significance and precise extent of the perturbation in redox signaling cascades is poorly understood. We report that mdx dystrophic mice are able to activate a compensatory antioxidant response at the presymptomatic stage of the disease. In contrast, increased circulating levels of IL-6 perturb the redox signaling cascade, even prior to the necrotic stage, leading to severe features and progressive nature of muscular dystrophy.


Asunto(s)
Interleucina-6/sangre , Músculo Esquelético/metabolismo , Distrofia Muscular Animal/sangre , Transducción de Señal , Animales , Diafragma/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Músculo Esquelético/patología , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/patología , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Necrosis , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo
8.
Hum Mol Genet ; 26(14): 2781-2790, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28472288

RESUMEN

Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused by mutations in the dystrophin gene and characterized by progressive, lethal muscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of a master player of the anti-oxidant and anti-inflammatory response, namely NF-E2-related Factor 2, in muscle biopsies of DMD patients. We classified DMD patients in two age groups (Class I, 0-2 years and Class II, 2-9 years), in order to evaluate the antioxidant pathway expression during the disease progression. We observed that altered enzymatic antioxidant responses, increased levels of oxidized glutathione and oxidative damage are differently modulated in the two age classes of patients and well correlate with the severity of pathology. Interestingly, we also observed a modulation of relevant markers of the inflammatory response, such as heme oxygenase 1 and Inteleukin-6 (IL-6), suggesting a link between oxidative stress and chronic inflammatory response. Of note, using a transgenic mouse model, we demonstrated that IL-6 overexpression parallels the antioxidant expression profile and the severity of dystrophic muscle observed in DMD patients. This study advances our understanding of the pathogenic mechanisms underlying DMD and defines the critical role of oxidative stress on muscle wasting with clear implications for disease pathogenesis and therapy in human.


Asunto(s)
Distrofia Muscular de Duchenne/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/fisiología , Animales , Antioxidantes/metabolismo , Niño , Preescolar , Modelos Animales de Enfermedad , Distrofina/genética , Distrofina/metabolismo , Femenino , Glutatión/genética , Glutatión/metabolismo , Humanos , Lactante , Recién Nacido , Inflamación/genética , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Factor 2 Relacionado con NF-E2/genética , Oxidación-Reducción , Transducción de Señal
9.
J Cell Biol ; 211(1): 77-90, 2015 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-26438828

RESUMEN

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre-messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMAΔ7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMAΔ7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3' splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Atrofia Muscular Espinal/metabolismo , Proteínas de Unión al ARN/fisiología , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo , Animales , Secuencia de Bases , Femenino , Células HEK293 , Ribonucleoproteína Nuclear Heterogénea A1 , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Neuronas Motoras/metabolismo , Atrofia Muscular Espinal/genética , Empalme del ARN , Médula Espinal/patología
10.
Hum Mol Genet ; 24(21): 6041-53, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26251044

RESUMEN

Duchenne muscular dystrophy (DMD) is characterized by progressive lethal muscle degeneration and chronic inflammatory response. The mdx mouse strain has served as the animal model for human DMD. However, while DMD patients undergo extensive necrosis, the affected muscles of adult mdx mice rapidly regenerates and regains structural and functional integrity. The basis for the mild effects observed in mice compared with the lethal consequences in humans remains unknown. In this study, we provide evidence that interleukin-6 (IL-6) is causally linked to the pathogenesis of muscular dystrophy. We report that forced expression of IL-6, in the adult mdx mice, recapitulates the severe phenotypic characteristics of DMD in humans. Increased levels of IL-6 exacerbate the dystrophic muscle phenotype, sustaining inflammatory response and repeated cycles of muscle degeneration and regeneration, leading to exhaustion of satellite cells. The mdx/IL6 mouse closely approximates the human disease and more faithfully recapitulates the disease progression in humans. This study promises to significantly advance our understanding of the pathogenic mechanisms that lead to DMD.


Asunto(s)
Interleucina-6/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Animales , Regulación hacia Abajo , Interleucina-6/genética , Ratones , Ratones Endogámicos mdx , Desarrollo de Músculos , Músculo Esquelético/patología , Fenotipo , Proteínas Serina-Treonina Quinasas/metabolismo , Células Satélite del Músculo Esquelético/patología , Células Madre/patología , Quinasa de Factor Nuclear kappa B
11.
EBioMedicine ; 2(4): 285-93, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26137572

RESUMEN

The anti-inflammatory agents glucocorticoids (GC) are the only available treatment for Duchenne muscular dystrophy (DMD). However, long-term GC treatment causes muscle atrophy and wasting. Thus, targeting specific mediator of inflammatory response may be more specific, more efficacious, and with fewer side effects. The pro-inflammatory cytokine interleukin (IL) 6 is overproduced in patients with DMD and in the muscle of mdx, the animal model for human DMD. We tested the ability of inhibition of IL6 activity, using an interleukin-6 receptor (Il6r) neutralizing antibody, to ameliorate the dystrophic phenotype. Blockade of endogenous Il6r conferred on dystrophic muscle resistance to degeneration and alleviated both morphological and functional consequences of the primary genetic defect. Pharmacological inhibition of IL6 activity leaded to changes in the dystrophic muscle environment, favoring anti-inflammatory responses and improvement in muscle repair. This resulted in a functional homeostatic maintenance of dystrophic muscle. These data provide an alternative pharmacological strategy for treatment of DMD and circumvent the major problems associated with conventional therapy.


Asunto(s)
Músculos/patología , Músculos/fisiopatología , Distrofia Muscular Animal/patología , Distrofia Muscular Animal/fisiopatología , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Duchenne/fisiopatología , Receptores de Interleucina-6/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Homeostasis , Inflamación/complicaciones , Inflamación/patología , Interleucina-6/sangre , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Distrofia Muscular Animal/sangre , Distrofia Muscular de Duchenne/sangre , Necrosis , Fenotipo , Receptores de Interleucina-6/metabolismo
12.
Front Aging Neurosci ; 7: 69, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25999854

RESUMEN

Duchenne muscular dystrophy (DMD) is a X-linked genetic disease in which the absence of dystrophin leads to progressive lethal skeletal muscle degeneration. It has been demonstrated that among genes which are important for proper muscle development and function, micro-RNAs (miRNAs) play a crucial role. Moreover, altered levels of miRNAs were found in several muscular disorders, including DMD. A specific group of miRNAs, whose expression depends on dystrophin levels and whose deregulation explains several DMD pathogenetic traits, has been identified. Here, we addressed whether the anabolic activity of mIGF-1 on dystrophic muscle is associated with modulation of microRNAs expression. We demonstrated that some microRNAs are strictly linked to the dystrophin expression and are not modulated by mIGF-1 expression. In contrast, local expression of mIGF-1 promotes the modulation of other microRNAs, such as miR-206 and miR-24, along with the modulation of muscle specific genes, which are associated with maturation of regenerating fibers and with the stabilization of the differentiated muscle phenotype. These data suggest that mIGF-1, modifying the expression of some of the active players of muscle homeostasis, is able, even in absence of dystrophin expression, to activate circuitries that confer robustness to dystrophic muscle.

13.
Biomed Res Int ; 2014: 235426, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24971321

RESUMEN

Skeletal muscle atrophy occurs during disuse and aging, or as a consequence of chronic diseases such as cancer and diabetes. It is characterized by progressive loss of muscle tissue due to hypotrophic changes, degeneration, and an inability of the regeneration machinery to replace damaged myofibers. Tumor necrosis factor (TNF) is a proinflammatory cytokine known to mediate muscle atrophy in many chronic diseases and to inhibit skeletal muscle regeneration. In this study, we investigated the role of Arg-vasopressin-(AVP-)dependent pathways in muscles in which atrophy was induced by local overexpression of TNF. AVP is a potent myogenesis-promoting factor and is able to enhance skeletal muscle regeneration by stimulating Ca(2+)/calmodulin-dependent kinase and calcineurin signaling. We performed morphological and molecular analyses and demonstrated that local over-expression of the AVP receptor V1a enhances regeneration of atrophic muscle. By upregulating the regeneration/differentiation markers, modulating the inflammatory response, and attenuating fibrogenesis, the stimulation of AVP-dependent pathways creates a favourable environment for efficient and sustained muscle regeneration and repair even in the presence of elevated levels of TNF. This study highlights a novel in vivo role for AVP-dependent pathways, which may represent an interesting strategy to counteract muscle decline in aging or in muscular pathologies.


Asunto(s)
Arginina Vasopresina/metabolismo , Atrofia Muscular/metabolismo , Receptores de Vasopresinas/metabolismo , Regeneración , Transducción de Señal , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Atrofia Muscular/inducido químicamente , Atrofia Muscular/patología , Receptores de Vasopresinas/genética , Factores de Necrosis Tumoral/genética , Factores de Necrosis Tumoral/metabolismo
14.
Neurol Res ; 33(10): 998-1009, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22196751

RESUMEN

OBJECTIVE: To compare the effects of isokinetic (ISO-K) and vibrational-proprioceptive (VIB) trainings on muscle mass and strength. METHODS: In 29 ISO-K- or VIB-trained young athletes we evaluated: force, muscle fiber morphometry, and gene expression of muscle atrophy/hypertrophy cell signaling. RESULTS: VIB training increased the maximal isometric unilateral leg extension force by 48·1%. ISO-K training improved the force by 24·8%. Both improvements were statistically significant (Pâ©¿0·01). The more functional effectiveness of the VIB training in comparison with the ISO-K training was shown by the statistical significance changes only in VIB group in: rate of force development in time segment 0-50 ms (P<0·001), squat jump (P<0·05) and 30-m acceleration running test (P<0·05). VIB training induced a highly significant increase of mean diameter of fast fiber (+9%, P<0·001), but not of slow muscle fibers (-3%, not significant). No neural cell adhesion molecule-positive (N-CAM(+)) and embryonic myosin heavy chain-positive (MHC-emb(+)) myofibers were detected. VIB induced a significant twofold increase (P<0·05) of the skeletal muscle isoform insulin-like growth factor-1 (IGF-1) Ec mRNA. Atrogin-1 and muscle ring finger-1 (MuRF-1) did not change, but myostatin was strongly downregulated after VIB training (P<0·001). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression increased in post-training groups, but only in VIB reached statistical significance (+228%, P<0·05). DISCUSSION: We demonstrated that both trainings are effective and do not induce muscle damage. Only VIB-trained group showed statistical significance increase of hypertrophy cell signaling pathways (IGF-1Ec and PGC-1α upregulation, and myostatin downregulation) leading to hypertrophy of fast twitch muscle fibers.


Asunto(s)
Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Atrofia Muscular/patología , Entrenamiento de Fuerza/métodos , Transducción de Señal/fisiología , Deportes/fisiología , Adulto , Humanos , Hipertrofia/etiología , Hipertrofia/patología , Masculino , Fibras Musculares Esqueléticas/citología , Proteínas Musculares/genética , Atrofia Muscular/etiología , Adulto Joven
15.
Endocr Dev ; 14: 29-37, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19293573

RESUMEN

In the last decade, dramatic progress has been made in elucidating the molecular defects underlying a number of muscle diseases. With the characterization of mutations responsible for muscle dysfunction in several inherited pathologies, and the identification of novel signaling pathways, subtle alterations in which can lead to significant defects in muscle metabolism, the field is poised to devise successful strategies for treatment of this debilitating and often fatal group of human ailments. Yet progress has been slow in therapeutic applications of our newly gained knowledge. The complexity of muscle types, the intimate relationship between structural integrity and mechanical function, and the sensitivity of skeletal muscle to metabolic perturbations have impeded rapid progress in successful clinical intervention. The relatively poor regenerative properties of striated muscle compound the devastating effects of muscle degeneration. Perhaps the most difficult hurdle is the sheer volume of tissue that must be treated to effect a significant improvement in quality of life. Recent studies on the role of insulin-like growth factor-1 in skeletal muscle growth and homeostasis have excited new interest in this important mediator of anabolic pathways and suggest promising new avenues for intervention in catabolic disease. In this review, we will discuss the potential therapeutic role of local insulin-like growth factor 1 in the treatment of muscle wasting associated with muscle diseases.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/metabolismo , Músculo Esquelético/metabolismo , Enfermedades Musculares , Transducción de Señal/fisiología , Humanos , Enfermedades Musculares/genética , Enfermedades Musculares/metabolismo , Enfermedades Musculares/terapia
16.
FASEB J ; 21(7): 1393-402, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17264161

RESUMEN

Muscle regeneration following injury is characterized by myonecrosis accompanied by local inflammation, activation of satellite cells, and repair of injured fibers. The resolution of the inflammatory response is necessary to proceed toward muscle repair, since persistence of inflammation often renders the damaged muscle incapable of sustaining efficient muscle regeneration. Here, we show that local expression of a muscle-restricted insulin-like growth factor (IGF)-1 (mIGF-1) transgene accelerates the regenerative process of injured skeletal muscle, modulating the inflammatory response, and limiting fibrosis. At the molecular level, mIGF-1 expression significantly down-regulated proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, and modulated the expression of CC chemokines involved in the recruitment of monocytes/macrophages. Analysis of the underlying molecular mechanisms revealed that mIGF-1 expression modulated key players of inflammatory response, such as macrophage migration inhibitory factor (MIF), high mobility group protein-1 (HMGB1), and transcription NF-kappaB. The rapid restoration of injured mIGF-1 transgenic muscle was also associated with connective tissue remodeling and a rapid recovery of functional properties. By modulating the inflammatory response and reducing fibrosis, supplemental mIGF-1 creates a qualitatively different environment for sustaining more efficient muscle regeneration and repair.


Asunto(s)
Quimiocinas/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Factor I del Crecimiento Similar a la Insulina/fisiología , Músculo Esquelético/fisiología , Regeneración , Animales , Secuencia de Bases , Técnica del Anticuerpo Fluorescente , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Músculo Esquelético/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
17.
J Cell Biol ; 168(2): 193-9, 2005 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-15657392

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective degeneration of motor neurons, atrophy, and paralysis of skeletal muscle. Although a significant proportion of familial ALS results from a toxic gain of function associated with dominant SOD1 mutations, the etiology of the disease and its specific cellular origins have remained difficult to define. Here, we show that muscle-restricted expression of a localized insulin-like growth factor (Igf) -1 isoform maintained muscle integrity and enhanced satellite cell activity in SOD1(G93A) transgenic mice, inducing calcineurin-mediated regenerative pathways. Muscle-specific expression of local Igf-1 (mIgf-1) isoform also stabilized neuromuscular junctions, reduced inflammation in the spinal cord, and enhanced motor neuronal survival in SOD1(G93A) mice, delaying the onset and progression of the disease. These studies establish skeletal muscle as a primary target for the dominant action of inherited SOD1 mutation and suggest that muscle fibers provide appropriate factors, such as mIgf-1, for neuron survival.


Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Factor I del Crecimiento Similar a la Insulina/fisiología , Neuronas Motoras/metabolismo , Músculo Esquelético/metabolismo , Agrina/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/mortalidad , Animales , Astrocitos/metabolismo , Northern Blotting , Western Blotting , Calcineurina/genética , Calcineurina/metabolismo , Sistema Nervioso Central/química , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Desmina/metabolismo , Modelos Animales de Enfermedad , Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Inmunohistoquímica , Factor I del Crecimiento Similar a la Insulina/genética , Ratones , Ratones Transgénicos , Neuronas Motoras/patología , Fibras Musculares Esqueléticas/citología , Músculo Esquelético/química , Músculo Esquelético/patología , Cadenas Pesadas de Miosina/metabolismo , Unión Neuromuscular/metabolismo , Factor de Transcripción PAX7 , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Células Satélite del Músculo Esquelético/química , Células Satélite del Músculo Esquelético/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Tasa de Supervivencia , Factor de Necrosis Tumoral alfa/metabolismo , Caminata
18.
Proc Natl Acad Sci U S A ; 101(5): 1206-10, 2004 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-14745025

RESUMEN

We investigated the mechanism whereby expression of a transgene encoding a locally acting isoform of insulin-like growth factor 1 (mIGF-1) enhances repair of skeletal muscle damage. Increased recruitment of proliferating bone marrow cells to injured MLC/mIgf-1 transgenic muscles was accompanied by elevated bone marrow stem cell production in response to distal trauma. Regenerating MLC/mIgf-1 transgenic muscles contained increased cell populations expressing stem cell markers, exhibited accelerated myogenic differentiation, expressed markers of regeneration and readily converted cocultured bone marrow to muscle. These data implicate mIGF-1 as a powerful enhancer of the regeneration response, mediating the recruitment of bone marrow cells to sites of tissue damage and augmenting local repair mechanisms.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/fisiología , Músculos/fisiología , Regeneración/fisiología , Células Madre/fisiología , Animales , Células de la Médula Ósea/fisiología , Antígeno CD11b/análisis , Movimiento Celular , Antígenos Comunes de Leucocito/análisis , Ratones , Ratones Transgénicos , Isoformas de Proteínas
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