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1.
Am J Physiol Cell Physiol ; 321(2): C288-C296, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34191629

RESUMEN

Impaired oxidative capacity and mitochondrial function contribute to the dystrophic pathology in muscles of patients with Duchenne muscular dystrophy (DMD) and in relevant mouse models of the disease. Emerging evidence suggests an association between disrupted core clock expression and mitochondrial quality control, but this has not been established in muscles lacking dystrophin. We examined the diurnal regulation of muscle core clock and mitochondrial quality control expression in dystrophin-deficient C57BL/10ScSn-Dmdmdx (mdx) mice, an established model of DMD. Male C57BL/10 (BL/10; n = 18) and mdx mice (n = 18) were examined every 4 h beginning at the dark cycle. Throughout the entire light-dark cycle, extensor digitorum longus (EDL) muscles from mdx mice had decreased core clock mRNA expression (Arntl, Cry1, Cry2, Nr1d2; P < 0.05) and disrupted mitochondrial quality control mRNA expression related to biogenesis (decreased; Ppargc1a, Esrra; P < 0.05), fission (increased; Dnm1l; P < 0.01), fusion (decreased; Opa1, Mfn1; P < 0.05), and autophagy/mitophagy (decreased: Bnip3; P < 0.05; increased: Becn1; P < 0.05). Cosinor analysis revealed a decrease in the rhythmicity parameters mesor and amplitude for Arntl, Cry1, Cry2, Per2, and Nr1d1 (P < 0.001) in mdx mice. Diurnal oscillations in Esrra, Sirt1, Map1lc3b, and Sqstm1 were absent in mdx mice, along with decreased mesor and amplitude of Ppargc1a mRNA expression (P < 0.01). The expression of proteins involved in mitochondrial biogenesis (decreased: PPARGC1A, P < 0.05) and autophagy/mitophagy (increased: MAP1LC3BII, SQSTM1, BNIP3; P < 0.05) were also dysregulated in tibialis anterior muscles of mdx mice. These findings suggest that dystrophin deficiency in mdx mice impairs the regulation of the core clock and mitochondrial quality control, with relevance to DMD and related disorders.


Asunto(s)
Distrofina/deficiencia , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/fisiopatología , Animales , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne/metabolismo , Utrofina/deficiencia
2.
Curr Opin Clin Nutr Metab Care ; 20(4): 237-242, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28375879

RESUMEN

PURPOSE OF REVIEW: The review summarizes the recent literature on the role of glycine in skeletal muscle during times of stress. RECENT FINDINGS: Supplemental glycine protects muscle mass and function under pathological conditions. In addition, mitochondrial dysfunction in skeletal muscle leads to increased cellular serine and glycine production and activation of NADPH-generating pathways and glutathione metabolism. These studies highlight how glycine availability modulates cellular homeostasis and redox status. SUMMARY: Recent studies demonstrate that supplemental glycine effectively protects muscles in a variety of wasting models, including cancer cachexia, sepsis, and reduced caloric intake. The underlying mechanisms responsible for the effects of glycine remain unclear but likely involve receptor-mediated responses and modulation of intracellular metabolism. Future research to understand these mechanisms will provide insight into glycine's therapeutic potential. Our view is that glycine holds considerable promise for improving health by protecting muscles during different wasting conditions.


Asunto(s)
Glicina/metabolismo , Homeostasis/fisiología , Músculo Esquelético/metabolismo , Animales , Antiinflamatorios , Suplementos Dietéticos , Glicina/administración & dosificación , Humanos , Enfermedades Metabólicas/prevención & control , Ratones , Atrofia Muscular/metabolismo , Oxidación-Reducción , Receptores de Glicina/fisiología , Síndrome Debilitante/prevención & control
3.
Eur J Appl Physiol ; 117(7): 1463-1472, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28493029

RESUMEN

PURPOSE: The aim of the study was to determine whether higher fibrosis markers in skeletal muscle of older adults are accompanied by increased expression of components of the canonical TGF-ß signal transduction pathway. METHODS: Fourteen healthy young (21-35 years; 9 males and 5 females) and seventeen older (55-75 years; 9 males and 8 females) participants underwent vastus lateralis biopsies to determine intramuscular mRNA and protein expression of fibrogenic markers and TGF-ß signaling molecules related to TGF-ß1 and myostatin. RESULTS: Expression of mRNA encoding the pro-fibrotic factors; axin 2, collagen III, ß-catenin and fibronectin, were all significantly higher (all p < 0.05) in the older participants (350, 170, 298, and 641%, respectively). Furthermore, axin 2 and ß-catenin mRNA were significantly higher in older females than older males (p < 0.05). Gene expression of ActRIIB, myostatin, and TGF-ß1 were higher in older adults compared to younger adults (all p < 0.05). There was, however, no difference in the total protein content of myostatin, myoD or myogenin (all p > 0.05), whereas Smad3 protein phosphorylation was 48% lower (p < 0.05) in muscle from older adults. CONCLUSIONS: Increased abundance of mRNA of fibrotic markers was observed in muscle from older adults and was partly accompanied by altered abundance of pro-fibrotic ligands in a sex specific manner.


Asunto(s)
Envejecimiento/metabolismo , Colágeno Tipo III/metabolismo , Fibronectinas/metabolismo , Músculo Esquelético/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Adulto , Anciano , Proteína Axina/genética , Proteína Axina/metabolismo , Colágeno Tipo III/genética , Femenino , Fibronectinas/genética , Fibrosis , Humanos , Masculino , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/patología , Miostatina/genética , Miostatina/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores Sexuales , Proteína smad3/genética , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/genética , beta Catenina/genética , beta Catenina/metabolismo
4.
Am J Physiol Endocrinol Metab ; 310(11): E970-81, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27094036

RESUMEN

Amino acids, especially leucine, potently stimulate protein synthesis and reduce protein breakdown in healthy skeletal muscle and as a result have received considerable attention as potential treatments for muscle wasting. However, the normal anabolic response to amino acids is impaired during muscle-wasting conditions. Although the exact mechanisms of this anabolic resistance are unclear, inflammation and ROS are believed to play a central role. The nonessential amino acid glycine has anti-inflammatory and antioxidant properties and preserves muscle mass in calorie-restricted and tumor-bearing mice. We hypothesized that glycine would restore the normal muscle anabolic response to amino acids under inflammatory conditions. Relative rates of basal and leucine-stimulated protein synthesis were measured using SUnSET methodology 4 h after an injection of 1 mg/kg lipopolysaccharide (LPS). Whereas leucine failed to stimulate muscle protein synthesis in LPS-treated mice pretreated with l-alanine (isonitrogenous control), leucine robustly stimulated protein synthesis (+51%) in mice pretreated with 1 g/kg glycine. The improvement in leucine-stimulated protein synthesis was accompanied by a higher phosphorylation status of mTOR, S6, and 4E-BP1 compared with l-alanine-treated controls. Despite its known anti-inflammatory action in inflammatory cells, glycine did not alter the skeletal muscle inflammatory response to LPS in vivo or in vitro but markedly reduced DHE staining intensity, a marker of oxidative stress, in muscle cross-sections and attenuated LPS-induced wasting in C2C12 myotubes. Our observations in male C57BL/6 mice suggest that glycine may represent a promising nutritional intervention for the attenuation of skeletal muscle wasting.


Asunto(s)
Glicina/administración & dosificación , Leucina/administración & dosificación , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/metabolismo , Miositis/tratamiento farmacológico , Miositis/metabolismo , Enfermedad Aguda , Anabolizantes/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos , Sinergismo Farmacológico , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/biosíntesis , Atrofia Muscular/patología , Miositis/patología , Resultado del Tratamiento
5.
Exerc Immunol Rev ; 22: 94-109, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26859514

RESUMEN

Muscle atrophy is caused by an imbalance in contractile protein synthesis and degradation which can be triggered by various conditions including Type 2 Diabetes Mellitus (T2DM). Reduced muscle quality in patients with T2DM adversely affects muscle function, the capacity to perform activities of daily living, quality of life and ultimately may increase the risk of premature mortality. Systemic inflammation initiated by obesity and prolonged overnutrition not only contributes to insulin resistance typical of T2DM, but also promotes muscle atrophy via decreased muscle protein synthesis and increased ubiquitin-proteasome, lysosomal-proteasome and caspase 3- mediated protein degradation. Emerging evidence suggests that the inflammation-sensitive Nuclear Factor κ B (NF-κB) and Signal Transducer and Activator of Transcription 3 (STAT3) pathways may contribute to muscle atrophy in T2DM. In contrast, exercise appears to be an effective tool in promoting muscle hypertrophy, in part due to its effect on systemic and local (skeletal muscle) inflammation. The current review discusses the role inflammation plays in muscle atrophy in T2DM and the role of exercise training in minimising the effect of inflammatory markers on skeletal muscle. We also report original data from a cohort of obese patients with T2DM compared to age-matched controls and demonstrate that patients with T2DM have 60% higher skeletal muscle expression of the atrophy transcription factor FoxO1. This review concludes that inflammatory pathways in muscle, in particular, NF-κB, potentially contribute to T2DM-mediated muscle atrophy. Further in-vivo and longitudinal human research is required to better understand the role of inflammation in T2DM-mediated atrophy and the anti-inflammatory effect of exercise training under these conditions.


Asunto(s)
Diabetes Mellitus Tipo 2 , Actividades Cotidianas , Ejercicio Físico , Genes Sintéticos , Humanos , Músculo Esquelético , Atrofia Muscular , FN-kappa B , Calidad de Vida , Proteínas Recombinantes
6.
Am J Physiol Endocrinol Metab ; 309(1): E72-83, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25968575

RESUMEN

Resistance training (RT) has the capacity to increase skeletal muscle mass, which is due in part to transient increases in the rate of muscle protein synthesis during postexercise recovery. The role of ribosome biogenesis in supporting the increased muscle protein synthetic demands is not known. This study examined the effect of both a single acute bout of resistance exercise (RE) and a chronic RT program on the muscle ribosome biogenesis response. Fourteen healthy young men performed a single bout of RE both before and after 8 wk of chronic RT. Muscle cross-sectional area was increased by 6 ± 4.5% in response to 8 wk of RT. Acute RE-induced activation of the ERK and mTOR pathways were similar before and after RT, as assessed by phosphorylation of ERK, MNK1, p70S6K, and S6 ribosomal protein 1 h postexercise. Phosphorylation of TIF-IA was also similarly elevated following both RE sessions. Cyclin D1 protein levels, which appeared to be regulated at the translational rather than transcriptional level, were acutely increased after RE. UBF was the only protein found to be highly phosphorylated at rest after 8 wk of training. Also, muscle levels of the rRNAs, including the precursor 45S and the mature transcripts (28S, 18S, and 5.8S), were increased in response to RT. We propose that ribosome biogenesis is an important yet overlooked event in RE-induced muscle hypertrophy that warrants further investigation.


Asunto(s)
Adaptación Fisiológica/fisiología , Músculo Esquelético/patología , Entrenamiento de Fuerza , Ribosomas/fisiología , Adolescente , Adulto , Metabolismo Energético/fisiología , Humanos , Hipertrofia , Masculino , Redes y Vías Metabólicas , Músculo Esquelético/metabolismo , Iniciación de la Cadena Peptídica Traduccional/fisiología , Descanso/fisiología , Adulto Joven
7.
J Nutr ; 145(5): 900-6, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25740910

RESUMEN

BACKGROUND: Increasing arginine (Arg) availability reduces atrophy in cultured skeletal muscle cells. Supplementation with its metabolic precursor citrulline (Cit) is more effective at improving skeletal muscle Arg concentrations. OBJECTIVE: We tested the hypothesis that Cit supplementation would attenuate skeletal muscle atrophy and loss of function during hindlimb immobilization in mice. METHODS: Male C57BL/6JArc mice underwent 14 d of unilateral hindlimb immobilization/plaster casting and were supplemented with ~0.81 g Cit · kg⁻¹ · d⁻¹ (CIT group) or Ala (ALA group) mixed into their food. The uncasted contralateral limb (internal control) and an uncasted group (CON) served as controls. Muscle atrophy was evaluated with mass, fiber area, and in situ muscle function. RESULTS: Tibialis anterior (TA) muscle mass [ALA: 37.6 ± 0.92 mg; CIT: 38.3 ± 1.25 mg] and peak tetanic force (ALA: 1150 ± 38.5 mN; CIT: 1150 ± 52.0 mN) were lower (P < 0.001) in the ALA (53.9 ± 0.42 mg) and CIT (1760 ± 28.5 mN) groups than in the CON group. No difference was found between ALA and CIT groups for TA mass, fiber area, or peak force. The mRNA expression of the nitric oxide synthase 2, inducible (Nos2; ~15-fold) and B-cell chronic lymphoid leukemia/lymphoma 2/adenovirus E1B 19 kDa interacting protein 3 (Bnip3; ~17-fold) genes and the ratio of microtubule-associated protein light chain 3BII to 3BI (LC3BII:LC3BI) (50.5% ± 17.7%) were higher (P < 0.05) in the ALA group than in the CON group, suggesting increased autophagy. In the CIT group, Bnip3 mRNA was lower (-70%; P < 0.05) and Nos2 mRNA tended to be lower (-45%; P = 0.05) than in the ALA group, whereas LC3BII:LC3BI was not different from the CON group. CONCLUSIONS: Cit treatment of male mice did not affect therapeutically relevant outcome measures such as skeletal muscle mass and peak muscle force after 14 d of hindlimb immobilization.


Asunto(s)
Citrulina/uso terapéutico , Suplementos Dietéticos , Modelos Animales de Enfermedad , Proteínas Musculares/metabolismo , Debilidad Muscular/prevención & control , Músculo Esquelético/patología , Atrofia Muscular/prevención & control , Animales , Autofagia , Biomarcadores/metabolismo , Citrulina/metabolismo , Fijación de Fractura/efectos adversos , Regulación de la Expresión Génica , Miembro Posterior , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Proteínas Musculares/genética , Debilidad Muscular/metabolismo , Debilidad Muscular/patología , Debilidad Muscular/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Atrofia Muscular/fisiopatología , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Restricción Física/efectos adversos
8.
Amino Acids ; 46(12): 2643-52, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25096520

RESUMEN

Amino acids are potent regulators of muscle protein synthesis and breakdown and have received considerable attention for the treatment of muscle wasting conditions. Arginine is critically involved in numerous physiological functions including providing substrate for the production of creatine, urea and nitric oxide (NO) and in the synthesis of new proteins. However, little is known about the direct effects of arginine on skeletal muscle protein synthesis during catabolic conditions. The aims of this study were to determine whether exogenous arginine could protect skeletal muscle cells from wasting directly and whether this effect was dependent on production of NO and/or activation of the rapamycin-sensitive mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. To explore these aims, we deprived mature C2C12 myotubes from nutrients and growth factors by incubating them in HEPES buffered saline with arginine or equimolar concentrations of alanine (control). Our results show that arginine: increased the ratio of phosphorylated to total mTOR (146 %), S6 (40 %) and 4EBP1 (69 %); increased protein synthesis (69 %) during the first hour of treatment; and increased myotube diameter by ~15 %. Experiments using the NO synthase inhibitor L-NG-Nitroarginine Methyl Ester showed a NO-independent protection from muscle wasting. On the other hand, the mTORC1 inhibitor rapamycin prevented increases in phosphorylated S6, protein synthesis and myotube diameter. The activation of mTORC1 and protein synthesis by arginine was not associated with changes in the phosphorylation status of Akt, but rather increased the expression of the amino acid-sensitive type III PI3-kinase Vps34 signalling protein. These data support a direct role for arginine in the regulation of mTORC1 in skeletal muscle.


Asunto(s)
Arginina/metabolismo , Complejos Multiproteicos/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Óxido Nítrico/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Biosíntesis de Proteínas , Transducción de Señal
9.
JPEN J Parenter Enteral Nutr ; 48(4): 421-428, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38522007

RESUMEN

BACKGROUND: During critical illness skeletal muscle wasting occurs rapidly. Although beta-hydroxy-beta-methylbutyrate (HMB) is a potential treatment to attenuate this process, the plasma appearance and muscle concentration is uncertain. METHODS: This was an exploratory study nested within a blinded, parallel group, randomized clinical trial in which critically ill patients after trauma received enteral HMB (3 g daily) or placebo. Plasma samples were collected at 0, 60, and 180 min after study supplement administration on day 1. Needle biopsies of the vastus lateralis muscle were collected (baseline and day 7 of the HMB treatment intervention period). An external standard curve was used to calculate HMB concentrations in plasma and muscle. RESULTS: Data were available for 16 participants (male n = 12 (75%), median [interquartile range] age 50 [29-58] years) who received placebo and 18 participants (male n = 14 (78%), age 49 [34-55] years) who received HMB. Plasma HMB concentrations were similar at baseline but increased after HMB (T = 60 min: placebo 0.60 [0.44-1.31] µM; intervention 51.65 [22.76-64.72] µM). Paired muscle biopsies were collected from 11 participants (placebo n = 7, HMB n = 4). Muscle HMB concentrations were similar at baseline between groups (2.35 [2.17-2.95]; 2.07 [1.78-2.31] µM). For participants in the intervention group who had the repeat biopsy within 4 h of HMB administration, concentrations were greater (7.2 and 12.3 µM) than those who had the repeat biopsy >4 h after HMB (2.7 and 2.1 µM). CONCLUSION: In this exploratory study, enteral HMB administration increased plasma HMB availability. The small sample size limits interpretation of the muscle HMB findings.


Asunto(s)
Enfermedad Crítica , Nutrición Enteral , Músculo Esquelético , Valeratos , Humanos , Masculino , Persona de Mediana Edad , Valeratos/administración & dosificación , Enfermedad Crítica/terapia , Adulto , Nutrición Enteral/métodos , Femenino , Heridas y Lesiones/terapia , Heridas y Lesiones/complicaciones , Atrofia Muscular/etiología
10.
Eur J Appl Physiol ; 113(2): 509-17, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22806088

RESUMEN

Older adults have an increase in circulating markers of inflammation. The current study examined whether there is an increase in the expression of inflammatory markers within the vastus lateralis, a major locomotive muscle, of older adults, and if so, whether the reduction in muscle strength and aerobic capacity in older adults is related to increased muscle inflammation. Skeletal muscle biopsies were taken from older adults (n = 17, 67 ± 1.6 years) and young individuals (n = 16, 24 ± 0.6 years) under resting and fasting conditions. Muscle was analyzed for mRNA levels of intracellular inflammatory molecules (MCP1, TNFα and IL-1ß) and total cellular protein abundance of cytokines, chemokines and kinases (IL-6, IL-8, MCP1, TNFα, p65 (NF-κB), JNK1/2 and STAT3). MCP1 expression was significantly higher (p < 0.05; 50 %, mRNA and 40 %, protein) in elderly than younger participants, as was IL-8 (4 %). No detectable difference in kinase protein expression was observed for STAT3, JNK or p65 (NF-κB), TNFα or IL-6. Muscle strength was lower in the elderly compared to the young group (1.55 ± 0.17 vs. 2.56 ± 0.13 Nm/kg, p < 0.001). The elderly group also had a significantly lower VO(2peak) compared to the young group (24.9 ± 1.9 vs. 39.3 ± 1.9, p < 0.001), but muscle strength and VO(2peak) were not correlated with the examined inflammatory markers. Older adults have increased MCP1 (mRNA and protein abundance) and IL-8 (protein abundance) and also reduced muscle strength and VO(2peak). However, the reduction in muscle strength and VO(2peak) was not related to the increase in muscle inflammatory markers in this cohort.


Asunto(s)
Envejecimiento/inmunología , Mediadores de Inflamación/inmunología , Fuerza Muscular/inmunología , Músculo Esquelético/fisiopatología , Miositis/fisiopatología , Consumo de Oxígeno/inmunología , Adulto , Anciano , Biomarcadores/sangre , Femenino , Humanos , Masculino
11.
Am J Physiol Regul Integr Comp Physiol ; 302(6): R667-73, 2012 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-22189669

RESUMEN

Intense resistance exercise causes a significant inflammatory response. NF-κB has been identified as a prospective key transcription factor mediating the postexercise inflammatory response. The purpose of this study was to determine whether a single bout of intense resistance exercise regulates NF-κB signaling in human skeletal muscle. Muscle biopsy samples were obtained from the vastus lateralis of five recreationally active, but not strength-trained, males (21.9 ± 1.3 yr) prior to, and at 2 and 4 h following, a single bout of intense resistance exercise. A further five subjects (4 males, 1 female) (23 ± 0.89 yr) were recruited as a nonexercise control group to examine the effect of the muscle biopsy protocol on key markers of skeletal muscle inflammation. Protein levels of IκBα and phosphorylated NF-κB (p65), as well as the mRNA expression of inflammatory myokines monocyte chemoattractant protein 1 (MCP-1), IL-6, and IL-8 were measured. Additionally, NF-κB (p65) DNA binding to the promoter regions of MCP-1, IL-6, and IL-8 was investigated. IκBα protein levels decreased, while p-NF-κB (p65) protein levels increased 2 h postexercise and returned to near-baseline levels by 4-h postexercise. Immunohistochemical data verified these findings, illustrating an increase in p-NF-κB (p65) protein levels, and nuclear localization at 2 h postexercise. Furthermore, NF-κB DNA binding to MCP-1, IL-6, and IL-8 promoter regions increased significantly 2 h postexercise as did mRNA levels of these myokines. No significant change was observed in the nonexercise control group. These novel data provide evidence that intense resistance exercise transiently activates NF-κB signaling in human skeletal muscle during the first few hours postexercise. These findings implicate NF-κB in the transcriptional control of myokines known to be central to the postexercise inflammatory response.


Asunto(s)
Ejercicio Físico/fisiología , Músculo Esquelético/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/fisiología , Biopsia , Quimiocina CCL2/metabolismo , ADN/metabolismo , Femenino , Humanos , Proteínas I-kappa B/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Músculo Esquelético/patología , Inhibidor NF-kappaB alfa , Adulto Joven
12.
Muscle Nerve ; 46(3): 407-12, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22907232

RESUMEN

INTRODUCTION AND METHODS: This study compared changes in myokine and myogenic genes following resistance exercise (3 sets of 12 repetitions of maximal unilateral knee extension) in 20 elderly men (67.8 ± 1.0 years) and 15 elderly women (67.2 ± 1.5 years). RESULTS: Monocyte chemotactic protein (MCP)-1, macrophage inhibitory protein (MIP)-1ß, interleukin (IL)-6 and MyoD mRNA increased significantly (P < 0.05), whereas myogenin and myostatin mRNA decreased significantly after exercise in both groups. Macrophage-1 (Mac-1) and MCP-3 mRNA did not change significantly after exercise in either group. MIP-1ß, Mac-1 and myostatin mRNA were significantly higher before and after exercise in men compared with women. In contrast, MCP-3 and myogenin mRNA were significantly higher before and after exercise in the women compared with the men. CONCLUSIONS: In elderly individuals, gender influences the mRNA expression of certain myokines and growth factors, both at rest and after resistance exercise. These differences may influence muscle regeneration following muscle injury.


Asunto(s)
Ejercicio Físico/fisiología , Inflamación/metabolismo , Músculo Esquelético/metabolismo , Entrenamiento de Fuerza , Anciano , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL4/genética , Quimiocina CCL4/metabolismo , Quimiocina CCL7/genética , Quimiocina CCL7/metabolismo , Femenino , Expresión Génica , Humanos , Inflamación/fisiopatología , Interleucina-6/genética , Interleucina-6/metabolismo , Antígeno de Macrófago-1/genética , Antígeno de Macrófago-1/metabolismo , Masculino , Persona de Mediana Edad , Desarrollo de Músculos , Músculo Esquelético/fisiopatología , Miogenina/genética , Miogenina/metabolismo , Factores Sexuales
13.
J Cachexia Sarcopenia Muscle ; 13(3): 1541-1553, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35249268

RESUMEN

BACKGROUND: Oxidative stress is implicated in the pathophysiology of Duchenne muscular dystrophy (DMD, caused by mutations in the dystrophin gene), which is the most common and severe of the muscular dystrophies. To our knowledge, the distribution of iron, an important modulator of oxidative stress, has not been assessed in DMD. We tested the hypotheses that iron accumulation occurs in mouse models of DMD and that modulation of iron through the diet or chelation could modify disease severity. METHODS: We assessed iron distribution and total elemental iron using LA-ICP-MS on skeletal muscle cross-sections of 8-week-old Bl10 control mice and dystrophic mdx mice (with moderate dystrophy) and dystrophin/utrophin-null mice (dko, with severe dystrophy). In addition, mdx mice (4 weeks) were treated with either an iron chelator (deferiprone 150 mg/kg/day) or iron-enriched feed (containing 1% added iron as carbonyl iron). Immunoblotting was used to determine the abundance of iron- and mitochondria-related proteins. (Immuno)histochemical and mRNA assessments of fibrosis and inflammation were also performed. RESULTS: We observed a significant increase in total elemental iron in hindlimb muscles of dko mice (+50%, P < 0.05) and in the diaphragm of mdx mice (+80%, P < 0.05), with both tissues exhibiting severe pathology. Iron dyshomeostasis was further evidenced by an increase in the storage protein ferritin (dko: +39%, P < 0.05) and ferroportin compared with Bl10 control mice (mdx: +152% and dko: +175%, P < 0.05). Despite having features of iron overload, dystrophic muscles had lower protein expression of ALAS-1, the rate-limiting enzyme for haem synthesis (dko -44%, P < 0.05), and the haem-containing protein myoglobin (dko -54%, P < 0.05). Deferiprone treatment tended to decrease muscle iron levels in mdx mice (-30%, P < 0.1), which was associated with lower oxidative stress and fibrosis, but suppressed haem-containing proteins and mitochondrial content. Increasing iron via dietary intervention elevated total muscle iron (+25%, P < 0.05) but did not aggravate the pathology. CONCLUSIONS: Muscles from dystrophic mice have increased iron levels and dysregulated iron-related proteins that are associated with dystrophic pathology. Muscle iron levels were manipulated by iron chelation and iron enriched feed. Iron chelation reduced fibrosis and reactive oxygen species (ROS) but also suppressed haem-containing proteins and mitochondrial activity. Conversely, iron supplementation increased ferritin and haem-containing proteins but did not alter ROS, fibrosis, or mitochondrial activity. Further studies are required to investigate the contribution of impaired ferritin breakdown in the dysregulation of iron homeostasis in DMD.


Asunto(s)
Sobrecarga de Hierro , Distrofia Muscular de Duchenne , Animales , Deferiprona , Distrofina/genética , Ferritinas , Fibrosis , Hemo/metabolismo , Hierro/metabolismo , Quelantes del Hierro , Sobrecarga de Hierro/etiología , Ratones , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne/genética , Especies Reactivas de Oxígeno/metabolismo
14.
Cytokine ; 55(1): 104-9, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21478033

RESUMEN

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade has been identified as a crucial factor for myogenesis. The STAT3 isoform is essential for satellite cell migration and myogenic differentiation as it mediates the expression of muscle specific myogenic factors. The SOCS (suppressors of cytokine signaling) family of proteins down-regulates STAT activation. Primary human skeletal muscle cells were isolated and cultured to investigate the effect of SOCS3 adenoviral overexpression on myotube maturation. It was demonstrated that STAT3 inhibition did not influence myotube development or survival. Moreover, SOCS3 overexpression enhances the mRNA expression of downstream targets of STAT3, c-FOS and VEGF. These increases were correlated with enhanced mRNA expression of genes associated with muscle maturation and hypertrophy. Thus SOCS3 influences myoblast differentiation and SOCS3 may be significant in regulating the activity of genes previously identified as transcriptionally regulated by STAT3.


Asunto(s)
Desarrollo de Músculos , Músculo Esquelético/crecimiento & desarrollo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Actinas/genética , Actinas/metabolismo , Apoptosis/genética , Diferenciación Celular/genética , Regulación del Desarrollo de la Expresión Génica , Humanos , Masculino , Desarrollo de Músculos/genética , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/metabolismo , Miogenina/genética , Miogenina/metabolismo , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas
15.
J Cachexia Sarcopenia Muscle ; 12(2): 476-492, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33665974

RESUMEN

BACKGROUND: Oxidative stress is implicated in the insidious loss of muscle mass and strength that occurs with age. However, few studies have investigated the role of iron, which is elevated during ageing, in age-related muscle wasting and blunted repair after injury. We hypothesized that iron accumulation leads to membrane lipid peroxidation, muscle wasting, increased susceptibility to injury, and impaired muscle regeneration. METHODS: To examine the role of iron in age-related muscle atrophy, we compared the skeletal muscles of 3-month-old with 22- to 24-month-old 129SvEv FVBM mice. We assessed iron distribution and total elemental iron using laser ablation inductively coupled plasma mass spectrometry and Perls' stain on skeletal muscle cross-sections. In addition, old mice underwent ischaemia-reperfusion (IR) injury (90 min ischaemia), and muscle regeneration was assessed 14 days after injury. Immunoblotting was used to determine lipid peroxidation (4HNE) and iron-related proteins. To determine whether muscle iron content can be altered, old mice were treated with deferiprone (DFP) in the drinking water, and we assessed its effects on muscle regeneration after injury. RESULTS: We observed a significant increase in total elemental iron (+43%, P < 0.05) and lipid peroxidation (4HNE: +76%, P < 0.05) in tibialis anterior muscles of old mice. Iron was further increased after injury (adult: +81%, old: +135%, P < 0.05) and associated with increased lipid peroxidation (+41%, P < 0.05). Administration of DFP did not impact iron or measures of lipid peroxidation in skeletal muscle or modulate muscle mass. Increased muscle iron concentration and lipid peroxidation were associated with less efficient regeneration, evident from the smaller fibres in cross-sections of tibialis anterior muscles (-24%, P < 0.05) and an increased percentage of fibres with centralized nuclei (+4124%, P < 0.05) in muscles of old compared with adult mice. Administration of DFP lowered iron after IR injury (PRE: -32%, P < 0.05 and POST: -41%, P < 0.05), but did not translate to structural improvements. CONCLUSIONS: Muscles from old mice have increased iron levels, which are associated with increased lipid peroxidation, increased susceptibility to IR injury, and impaired muscle regeneration. Our results suggest that iron is involved in effective muscle regeneration, highlighting the importance of iron homeostasis in muscle atrophy and muscle repair.


Asunto(s)
Músculo Esquelético , Daño por Reperfusión , Animales , Hierro , Isquemia , Ratones , Regeneración
16.
Front Nutr ; 6: 172, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31803749

RESUMEN

Glycine supplementation can protect skeletal muscles of mice from cancer-induced wasting, but the mechanisms underlying this protection are not well-understood. The aim of this study was to determine whether exogenous glycine directly protects skeletal muscle cells from wasting. C2C12 muscle cells were exposed to non-inflammatory catabolic stimuli via two models: serum withdrawal (SF) for 48 h; or incubation in HEPES buffered saline (HBS) for up to 5 h. Cells were supplemented with glycine or equimolar concentrations of L-alanine. SF- and HBS-treated myotubes (with or without L-alanine) were ~20% and ~30% smaller than control myotubes. Glycine-treated myotubes were up to 20% larger (P < 0.01) compared to cells treated with L-alanine in both models of muscle cell atrophy. The mTORC1 inhibitor rapamycin prevented the glycine-stimulated protection of myotube diameter, and glycine-stimulated S6 phosphorylation, suggesting that mTORC1 signaling may be necessary for glycine's protective effects in vitro. Increasing glycine availability may be beneficial for muscle wasting conditions associated with inadequate nutrient intake.

17.
PLoS One ; 14(2): e0212880, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30811469

RESUMEN

Muscles of older animals are more susceptible to injury and regenerate poorly, in part due to a persistent inflammatory response. The janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway mediates inflammatory signaling and is tightly regulated by the suppressor of cytokine signaling (SOCS) proteins, especially SOCS3. SOCS3 expression is altered in the muscle of aged animals and may contribute to the persistent inflammation and impaired regeneration. To test this hypothesis, we performed myotoxic injuries on mice with a tamoxifen-inducible deletion of SOCS3 specifically within the muscle stem cell compartment. Muscle stem cell-specific SOCS3 deletion reduced muscle mass at 14 days post-injury (-14%, P < 0.01), altered the myogenic transcriptional program, and reduced myogenic fusion based on the number of centrally-located nuclei per muscle fiber. Despite the delay in myogenesis, muscles with a muscle stem cell-specific deletion of SOCS3 were still able to regenerate after a single bout or multiple bouts of myotoxic injury. A reduction in SOCS3 expression in muscle stem cells is unlikely to be responsible for the incomplete muscle repair in aged animals.


Asunto(s)
Envejecimiento/genética , Eliminación de Gen , Regeneración/efectos de los fármacos , Células Madre/citología , Proteína 3 Supresora de la Señalización de Citocinas/genética , Tamoxifeno/efectos adversos , Envejecimiento/metabolismo , Animales , Células Cultivadas , Femenino , Masculino , Ratones , Células Musculares/efectos de los fármacos , Células Musculares/fisiología , Factor de Transcripción PAX7/metabolismo , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo
18.
Sci Rep ; 9(1): 12982, 2019 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-31506484

RESUMEN

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease characterized by progressive muscle wasting and weakness and premature death. Glucocorticoids (e.g. prednisolone) remain the only drugs with a favorable impact on DMD patients, but not without side effects. We have demonstrated that glycine preserves muscle in various wasting models. Since glycine effectively suppresses the activity of pro-inflammatory macrophages, we investigated the potential of glycine treatment to ameliorate the dystrophic pathology. Dystrophic mdx and dystrophin-utrophin null (dko) mice were treated with glycine or L-alanine (amino acid control) for up to 15 weeks and voluntary running distance (a quality of life marker and strong correlate of lifespan in dko mice) and muscle morphology were assessed. Glycine increased voluntary running distance in mdx mice by 90% (P < 0.05) after 2 weeks and by 60% (P < 0.01) in dko mice co-treated with prednisolone over an 8 week treatment period. Glycine treatment attenuated fibrotic deposition in the diaphragm by 28% (P < 0.05) after 10 weeks in mdx mice and by 22% (P < 0.02) after 14 weeks in dko mice. Glycine treatment augmented the prednisolone-induced reduction in fibrosis in diaphragm muscles of dko mice (23%, P < 0.05) after 8 weeks. Our findings provide strong evidence that glycine supplementation may be a safe, simple and effective adjuvant for improving the efficacy of prednisolone treatment and improving the quality of life for DMD patients.


Asunto(s)
Modelos Animales de Enfermedad , Glicinérgicos/administración & dosificación , Glicina/administración & dosificación , Distrofia Muscular Animal/tratamiento farmacológico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Prednisolona/farmacología , Animales , Antiinflamatorios/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Ratones Noqueados , Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/patología , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología
20.
Clin Nutr ; 35(5): 1118-26, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-26431812

RESUMEN

BACKGROUND & AIM: Calorie restriction (CR) reduces co-morbidities associated with obesity, but also reduces lean mass thereby predisposing people to weight regain. Since we demonstrated that glycine supplementation can reduce inflammation and muscle wasting, we hypothesized that glycine supplementation during CR would preserve muscle mass in mice. METHODS: High-fat fed male C57BL/6 mice underwent 20 days CR (40% reduced calories) supplemented with glycine (1 g/kg/day; n = 15, GLY) or l-alanine (n = 15, ALA). Body composition and glucose tolerance were assessed and hindlimb skeletal muscles and epididymal fat were collected. RESULTS: Eight weeks of a high-fat diet (HFD) induced obesity and glucose intolerance. CR caused rapid weight loss (ALA: 20%, GLY: 21%, P < 0.01), reduced whole-body fat mass (ALA: 41%, GLY: 49% P < 0.01), and restored glucose tolerance to control values in ALA and GLY groups. GLY treated mice lost more whole-body fat mass (14%, p < 0.05) and epididymal fat mass (26%, P < 0.05), less lean mass (27%, P < 0.05), and had better preserved quadriceps muscle mass (4%, P < 0.01) than ALA treated mice after 20 d CR. Compared to the HFD group, pro-inflammatory genes were lower (P < 0.05), metabolic genes higher (P < 0.05) and S6 protein phosphorylation lower after CR, but not different between ALA and GLY groups. There were significant correlations between %initial fat mass (pre CR) and the mRNA expression of genes involved in inflammation (r = 0.51 to 0.68, P < 0.05), protein breakdown (r = -0.66 to -0.37, P < 0.05) and metabolism (r = -0.59 to -0.47, P < 0.05) after CR. CONCLUSION: Taken together, these findings suggest that glycine supplementation during CR may be beneficial for preserving muscle mass and stimulating loss of adipose tissue.


Asunto(s)
Restricción Calórica , Suplementos Dietéticos , Glicina/administración & dosificación , Obesidad/tratamiento farmacológico , Animales , Composición Corporal , Índice de Masa Corporal , Citocinas/genética , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Intolerancia a la Glucosa , Inflamación/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/prevención & control , Obesidad/etiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Aumento de Peso , Pérdida de Peso
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