RESUMO
Sarcopenia starts around the age of 40, causes the loss of 8% of muscle mass every 10 years, and is accompanied by functional deficit, chronic low-grade inflammation, and can result in several negative health outcomes. Considering the early and gradual onset of sarcopenia, the time window of the potential interventions could be crucial for the exertion of a beneficial effect. We recently showed that the long-term supplementation with Resveratrol contrasts sarcopenia in naturally ageing C57BL/6 mice. Aiming to understand the effects of a short term treatment, we administered intraperitoneally middle aged male mice with 20 mg/kg body weight Resveratrol daily for 5 weeks. Although we could not observe major differences in the histological properties of SKMs, we detected a significant decrease of Cox-2 in RES-treated muscles, confirming the anti-inflammatory action of Resveratrol, and suggesting that its anti-inflammatory action precedes modifications to SKM fibres.
Assuntos
Sarcopenia , Envelhecimento , Animais , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético , Resveratrol/farmacologia , Sarcopenia/tratamento farmacológicoRESUMO
A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver them to their destination. The GC is a hub organelle, crucial for organization of the other secretory pathway components. As a consequence, GC's form and function are key players in the pathogenesis of several disorders. Skeletal muscle (SKM) damage can be caused by defective protein modifications and traffic, as observed in some Limb girdle muscular dystrophies. Interestingly, in turn, muscle damage in Duchenne dystrophic SKM cells also includes the alteration of GC morphology. Based on the correlation between GC's form and function described in non-muscle diseases, we suggest a key role for this hub organelle also in the onset and progression of some SKM disorders. An altered GC could affect the secretory pathway via primary (e.g., mutation of a glycosylation enzyme), or secondary mechanisms (e.g., GC mis-localization in Duchenne muscles), which converge in SKM cell failure. This evidence induces considering the secretory pathway as a potential therapeutic target in the treatment of muscular dystrophies.
Assuntos
Distrofia Muscular do Cíngulo dos Membros , Distrofias Musculares , Humanos , Distrofias Musculares/metabolismo , Músculo Esquelético/metabolismo , Complexo de Golgi/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Fibras Musculares Esqueléticas/metabolismoRESUMO
KEY POINTS: Few days of unloading are sufficient to induce a decline of skeletal muscle mass and function; notably, contractile force is lost at a faster rate than muscle mass. The reasons behind this disproportionate loss of muscle force are still poorly understood. We provide strong evidence of two mechanisms only hypothesized until now for the rapid muscle force loss in only 10 days of bed rest. Our results show that an initial neuromuscular junction instability, accompanied by alterations in the innervation status and impairment of single fibre sarcoplasmic reticulum function contribute to the loss of contractile force in front of a preserved myofibrillar function and central activation capacity. Early onset of neuromuscular junction instability and impairment in calcium dynamics involved in excitation-contraction coupling are proposed as eligible determinants to the greater decline in muscle force than in muscle size during unloading. ABSTRACT: Unloading induces rapid skeletal muscle atrophy and functional decline. Importantly, force is lost at a much higher rate than muscle mass. We aimed to investigate the early determinants of the disproportionate loss of force compared to that of muscle mass in response to unloading. Ten young participants underwent 10 days of bed rest (BR). At baseline (BR0) and at 10 days (BR10), quadriceps femoris (QF) volume (VOL) and isometric maximum voluntary contraction (MVC) were assessed. At BR0 and BR10 blood samples and biopsies of vastus lateralis (VL) muscle were collected. Neuromuscular junction (NMJ) stability and myofibre innervation status were assessed, together with single fibre mechanical properties and sarcoplasmic reticulum (SR) calcium handling. From BR0 to BR10, QFVOL and MVC decreased by 5.2% (P = 0.003) and 14.3% (P < 0.001), respectively. Initial and partial denervation was detected from increased neural cell adhesion molecule (NCAM)-positive myofibres at BR10 compared with BR0 (+3.4%, P = 0.016). NMJ instability was further inferred from increased C-terminal agrin fragment concentration in serum (+19.2% at BR10, P = 0.031). Fast fibre cross-sectional area (CSA) showed a trend to decrease by 15% (P = 0.055) at BR10, while single fibre maximal tension (force/CSA) was unchanged. However, at BR10 SR Ca2+ release in response to caffeine decreased by 35.1% (P < 0.002) and 30.2% (P < 0.001) in fast and slow fibres, respectively, pointing to an impaired excitation-contraction coupling. These findings support the view that the early onset of NMJ instability and impairment in SR function are eligible mechanisms contributing to the greater decline in muscle force than in muscle size during unloading.
Assuntos
Cálcio , Retículo Sarcoplasmático , Humanos , Contração Muscular , Músculo Esquelético , Junção Neuromuscular , Músculo QuadrícepsRESUMO
We recently showed that the treatment with Resveratrol (RES) contrasts the effects of ageing on the skeletal muscle (SKM), reduces the appearance of tubular aggregates (TAs), and improves the fatigue resistance. Since fatigue resistance depends on the SKM capillary network, and RES has been described to improve vascularisation, we analysed the SKM capillarization in naturally ageing C57BL/6J male mice, fed with 0.04% RES in the diet for 6 months, which showed a better fatigue resistance in a previous work. Our data show an inverse correlation between the number of capillaries per fibre (CAF) and TAs in both control and treated type IIB fibres, and an increase of CAF in ageing SKM upon RES-treatment. The present work suggests that capillarization is one of the determinants of the development of TAs and fatigue resistance, and that RES can be considered a good candidate to counteract capillary rarefaction in the SKM tissue.
Assuntos
Envelhecimento/efeitos dos fármacos , Capilares/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Resveratrol/farmacologia , Animais , Capilares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Skeletal muscle aging is accompanied by mass reduction and functional decline, as a result of multiple factors, such as protein expression, morphology of organelles, metabolic equilibria, and neural communication. Skeletal muscles are formed by multiple fibers that express different Myosin Heavy Chains (MyHCs) and have different metabolic properties and different blood supply, with the purpose to adapt their contraction to the functional need. The fine interplay between the different fibers composing a muscle and its architectural organization determine its functional properties. Immunohistochemical and histochemical analyses of the skeletal muscle tissue, besides evidencing morphological characteristics, allow for the precise determination of protein expression and metabolic properties, providing essential information at the single-fiber level. Aiming to gain further knowledge on the influence of aging on skeletal muscles, we investigated the expression of the MyHCs, the Succinate Dehydrogenase (SDH) activity, and the presence of capillaries and Tubular Aggregates (TAs) in the tibialis anterior muscles of physiologically aging C57BL/6J mice aged 8 (adult), 18 (middle aged), and 24 months (old). We observed an increase of type-IIB fast-contracting fibers, an increase of the oxidative capacity of type-IIX and -IIA fibers, a general decrease of the capillarization, and the onset of TAs in type-IIB fibers. These data suggest that aging entails a selective modification of the muscle fiber profiles.
Assuntos
Envelhecimento , Metaboloma , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Adaptação Fisiológica , Fosfatase Alcalina/metabolismo , Animais , Capilares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Succinato Desidrogenase/metabolismoRESUMO
KEY POINTS: Disuse in older adults can critically decrease lower limb muscle power, leading to compromised mobility and overall quality of life. We studied how muscle power and its determinants (muscle mass, single muscle fibre properties and motor control) adapted to 2 weeks of disuse and subsequent 2 weeks of physical training in young and older people. Disuse decreased lower limb muscle power in both groups; however, different adaptations in single muscle fibre properties and co-contraction of leg muscles were observed between young and older individuals. Six physical training sessions performed after disuse promoted the recovery of muscle mass and power. However, they were not sufficient to restore muscle power to pre-disuse values in older individuals, suggesting that further countermeasures are required to counteract the disuse-induced loss of muscle power in older adults. ABSTRACT: Disuse-induced loss of muscle power can be detrimental in older individuals, seriously impairing functional capacity. In this study, we examined the changes in maximal explosive power (MEP) of lower limbs induced by a 14-day disuse (bed-rest, BR) and a subsequent 14-day retraining, to assess whether the impact of disuse was greater in older than in young men, and to analyse the causes of such adaptations. Sixteen older adults (Old: 55-65 years) and seven Young (18-30 years) individuals participated in this study. In a subgroup of eight Old subjects, countermeasures based on cognitive training and protein supplementation were applied. MEP was measured with an explosive ergometer, muscle mass was determined by magnetic resonance, motor control was studied by EMG, and single muscle fibres were analysed in vastus lateralis biopsy samples. MEP was â¼33% lower in Old than in Young individuals, and remained significantly lower (-19%) when normalized by muscle volume. BR significantly affected MEP in Old (-15%) but not in Young. Retraining tended to increase MEP; however, this intervention was not sufficient to restore pre-BR values in Old. Ankle co-contraction increased after BR in Old only, and remained elevated after retraining (+30%). Significant atrophy occurred in slow fibres in Old, and in fast fibres in Young. After retraining, the recovery of muscle fibre thickness was partial. The proposed countermeasures were not sufficient to affect muscle mass and power. The greater impact of disuse and smaller retraining-induced recovery observed in Old highlight the importance of designing suitable rehabilitation protocols for older individuals.
Assuntos
Extremidade Inferior/fisiologia , Força Muscular , Músculo Esquelético/fisiologia , Qualidade de Vida , Treinamento Resistido , Adulto , Repouso em Cama , Exercício Físico , Humanos , Imobilização , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Adulto JovemRESUMO
Here, we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy. These CASQ1 mutations affect conserved amino acids in position 44 (p.(Asp44Asn)), 103 (p.(Gly103Asp)), and 385 (p.(Ile385Thr)). Functional studies, based on turbidity and dynamic light scattering measurements at increasing Ca2+ concentrations, showed a reduced Ca2+ -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations and a slight increase in Ca2+ -dependent aggregation for the p.Ile385Thr. Accordingly, limited trypsin proteolysis assay showed that p.Asp44Asn and p.Gly103Asp were more susceptible to trypsin cleavage in the presence of Ca2+ in comparison with WT and p.Ile385Thr. Analysis of single muscle fibers of a patient carrying the p.Gly103Asp mutation showed a significant reduction in response to caffeine stimulation, compared with normal control fibers. Expression of CASQ1 mutations in eukaryotic cells revealed a reduced ability of all these CASQ1 mutants to store Ca2+ and a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca2+ entry. These results widen the spectrum of skeletal muscle diseases associated with CASQ1 and indicate that these mutations affect properties critical for correct Ca2+ handling in skeletal muscle fibers.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Cálcio/metabolismo , Variação Genética , Proteínas Mitocondriais/genética , Miopatias Congênitas Estruturais/genética , Adulto , Idoso , Sequência de Aminoácidos , Substituição de Aminoácidos , Proteínas de Ligação ao Cálcio/metabolismo , Calsequestrina , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/metabolismo , Modelos Moleculares , Músculo Esquelético/metabolismo , Mutação de Sentido Incorreto , Multimerização Proteica , Proteólise , Proteínas Recombinantes , Alinhamento de Sequência , Imagem com Lapso de Tempo , Sequenciamento Completo do GenomaRESUMO
KEY POINTS: Muscle atrophy is a debilitating condition that affects a high percentage of the population with a negative impact on quality of life. Dissecting the molecular level of the atrophy process, and the similarities/dissimilarities among different catabolic conditions, is a necessary step for designing specific countermeasures to attenuate/prevent muscle loss. The FoxO family transcription factors represent one of the most important regulators of atrophy programme stimulating the expression of many atrophy-related genes. The findings of the present study clearly indicate that the signalling network controlling the atrophy programme is specific for each catabolic condition. ABSTRACT: Muscle atrophy is a complex process that is in common with many different catabolic diseases including disuse/inactivity and ageing. The signalling pathways that control the atrophy programme in the different disuse/inactivity conditions have not yet been completely dissected. The inhibition of FoxO is considered to only partially spare muscle mass after denervation. The present study aimed: (i) to determine the involvement of FoxOs in hindlimb suspension disuse model; (ii) to define whether the molecular events of protein breakdown are shared among different unloaded muscles; and finally (iii) to compare the data obtained in this model with another model of inactivity such as denervation. Both wild-type and muscle-specific FoxO1,3,4 knockout (FoxO1,3,4-/- ) mice were unloaded for 3 and 14 days and muscles were characterized by functional, morphological, biochemical and molecular assays. The data obtained show that FoxOs are required for muscle loss and force drop during unloading. Moreover, we found that FoxO-dependent atrogenes vary in different unloaded muscles and that they diverge from denervation. The findings of the present study clearly indicate that the signalling network that controls the atrophy programme is specific for each catabolic condition.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Atrofia Muscular/metabolismo , Animais , Fatores de Transcrição Forkhead/genética , Elevação dos Membros Posteriores/efeitos adversos , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/etiologiaRESUMO
INTRODUCTION: The cellular prion protein (PrP(C) ) is commonly recognized as the precursor of prions, the infectious agents of the fatal transmissible spongiform encephalopathies, or prion diseases. Despite extensive effort, the physiological role of PrP(C) is still ambiguous. Evidence has suggested that PrP(C) is involved in different cellular functions, including peripheral nerve integrity and skeletal muscle physiology. METHODS: We analyzed the age-dependent influence of PrP(C) on treadmill test-based aerobic exercise capacity and on a series of morphological and metabolic parameters using wild-type and genetically modified mice of different ages expressing, or knockout (KO) for, PrP(C) . RESULTS: We found that aged PrP-KO mice displayed a reduction in treadmill performance compared with PrP-expressing animals, which was associated with peripheral nerve demyelination and alterations of skeletal muscle fiber type. CONCLUSION: PrP-KO mice have an age-dependent impairment of aerobic performance as a consequence of specific peripheral nerve and muscle alterations.
Assuntos
Envelhecimento , Doenças Neuromusculares/genética , Príons/metabolismo , Potenciais de Ação/genética , Adenosina Trifosfatases/metabolismo , Animais , Citrato (si)-Sintase/metabolismo , Modelos Animais de Doenças , Teste de Esforço , Regulação da Expressão Gênica/genética , Ácido Láctico/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/genética , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Força Muscular/genética , Músculo Esquelético/fisiopatologia , Cadeias Pesadas de Miosina/metabolismo , Condução Nervosa/genética , Doenças Neuromusculares/sangue , Doenças Neuromusculares/patologia , Doenças Neuromusculares/fisiopatologia , Príons/genética , Nervo Isquiático/patologia , Succinato Desidrogenase/metabolismoRESUMO
A missense mutation in the calsequestrin-1 gene (CASQ1) was found in a group of patients with a myopathy characterized by weakness, fatigue, and the presence of large vacuoles containing characteristic inclusions resulting from the aggregation of sarcoplasmic reticulum (SR) proteins. The mutation affects a conserved aspartic acid in position 244 (p.Asp244Gly) located in one of the high-affinity Ca(2+) -binding sites of CASQ1 and alters the kinetics of Ca(2+) release in muscle fibers. Expression of the mutated CASQ1 protein in COS-7 cells showed a markedly reduced ability in forming elongated polymers, whereas both in cultured myotubes and in in vivo mouse fibers induced the formation of electron-dense SR vacuoles containing aggregates of the mutant CASQ1 protein that resemble those observed in muscle biopsies of patients. Altogether, these results support the view that a single missense mutation in the CASQ1 gene causes the formation of abnormal SR vacuoles containing aggregates of CASQ1, and other SR proteins, results in altered Ca(2+) release in skeletal muscle fibers, and, hence, is responsible for the clinical phenotype observed in these patients.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Doenças por Armazenamento dos Lisossomos/metabolismo , Proteínas Mitocondriais/genética , Doenças Musculares/metabolismo , Mutação de Sentido Incorreto , Agregação Patológica de Proteínas/genética , Adulto , Animais , Células COS , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/química , Proteínas de Ligação ao Cálcio/metabolismo , Calsequestrina , Chlorocebus aethiops , Feminino , Humanos , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Fibras Musculares Esqueléticas/ultraestrutura , Doenças Musculares/genética , Doenças Musculares/patologia , Linhagem , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/ultraestrutura , Vacúolos/metabolismo , Vacúolos/ultraestrutura , Adulto JovemRESUMO
In the context of the increasing number of obese individuals, a major problem is represented by obesity and malnutrition in children. This condition is mainly ascribable to unbalanced diets characterized by high intakes of fat and sugar. Childhood obesity and malnutrition are not only associated with concurrent pathologies but potentially compromise adult life. Considering the strict correlation among systemic metabolism, obesity, and skeletal muscle health, we wanted to study the impact of juvenile malnutrition on the adult skeletal muscle. To this aim, 3-week-old C56BL/6 female and male mice were fed for 20 weeks on a high-fat. high-sugar diet, and their muscles were subjected to a histological evaluation. MyHCs expression, glycogen content, intramyocellular lipids, mitochondrial activity, and capillary density were analyzed on serial sections to obtain the metabolic profile. Our observations indicate that a high-fat, high-sugar diet alters the metabolic profile of skeletal muscles in a sex-dependent way and induces the increase in type II fibers, mitochondrial activity, and lipid content in males, while reducing the capillary density in females. These data highlight the sex-dependent response to nutrition, calling for the development of specific strategies and for a systematic inclusion of female subjects in basic and applied research in this field.
Assuntos
Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Músculo Esquelético , Animais , Feminino , Masculino , Dieta Hiperlipídica/efeitos adversos , Músculo Esquelético/metabolismo , Camundongos , Fatores Sexuais , Açúcares da Dieta , Glicogênio/metabolismo , Caracteres Sexuais , Metabolismo dos LipídeosRESUMO
Ageing is a biological process caused by the malfunctioning of multiple cellular mechanisms, ascribable to nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These ageing pillars have three common traits: (i) they appear during normal ageing; (ii) their experimental intensification accelerates ageing; and (iii) their experimental reduction delays ageing. The evidence that the elderly are more prone to develop pathologies such as cancer, diabetes and degenerative diseases, together with data showing that the elderly population is steadily increasing, has stimulated an important effort to find specific countermeasures to physiological ageing. Unfortunately, the investigation of ageing processes and the search for countermeasures in humans is very difficult. Therefore, researchers must rely on a wide range of experimental models that span from unicellular to more complex organisms. Unfortunately, experimental models are not devoid of pitfalls, flaws or obstacles that can have an impact in ageing research. In the present review we describe the most exploited experimental models in the field, such as in vitro, animal and human models, highlighting the characteristics that justify their application in the laboratory routine, and translation to human research.
Assuntos
Envelhecimento , Senescência Celular , Idoso , Animais , Humanos , Envelhecimento/patologia , Senescência Celular/fisiologia , Comunicação Celular , Células-Tronco , TelômeroRESUMO
Resveratrol is a natural polyphenol utilized in Chinese traditional medicine and thought to be one of the determinants of the "French Paradox". More recently, some groups evidenced its properties as a calorie-restriction mimetic, suggesting that its action passes through the modulation of skeletal muscle metabolism. Accordingly, the number of studies reporting the beneficial effects of resveratrol on skeletal muscle form and function, in both experimental models and humans, is steadily increasing. Although studies on animal models confer to resveratrol a good potential to ameliorate skeletal muscle structure, function and performance, clinical trials still do not provide clear-cut information. Here, we first summarize the effects of resveratrol on the distinct components of the skeletal muscle, such as myofibers, the neuromuscular junction, tendons, connective sheaths and the capillary bed. Second, we review clinical trials focused on the analysis of skeletal muscle parameters. We suggest that the heterogeneity in the response to resveratrol in humans could depend on sample characteristics, treatment modalities and parameters analyzed; as well, this heterogeneity could possibly reside in the complexity of skeletal muscle physiology. A systematic programming of treatment protocols and analyses could be helpful to obtain consistent results in clinical trials involving resveratrol administration.
Assuntos
Músculo Esquelético , Estilbenos , Animais , Humanos , Resveratrol/farmacologia , Resveratrol/metabolismo , Músculo Esquelético/metabolismo , Polifenóis/farmacologia , Restrição Calórica , Estilbenos/uso terapêuticoRESUMO
Human skeletal muscle atrophy and a disproportionate force loss occur within a few days of unloading in space and on Earth, but the underlying mechanisms are not fully understood. Disruption of neuromuscular junction homeostasis has been proposed as one of the possible causes. Here, we investigated the potential mechanisms involved in this neuromuscular disruption induced by a 10-day unilateral lower limb suspension (ULLS) in humans. Specifically, we investigated hemichannels' upregulation, neuromuscular junction and axonal damage, neurotrophins' receptor downregulation and inflammatory transcriptional signatures. Biomarkers were evaluated at local and systemic levels. At the sarcolemmal level, changes were found to be associated with an increased expression of connexin 43 and pannexin-1. Upregulation of the inflammatory transcripts revealed by deep transcriptomics was found after 10 days of ULLS. The destabilisation of the neuromuscular junction was not accompanied by changes in the secretion of the brain-derived neurotrophic factor and neurotrophin-4, while their receptor, BDNF/NT growth factors receptor (TrkB), decreased. Furthermore, at 5 days of ULLS, there was already a significant upregulation of the serum neurofilament light chain concentration, an established clinical biomarker of axonal injury. At 10 days of ULLS, other biomarkers of early denervation processes appeared. Hence, short periods of muscle unloading induce sarcolemmal hemichannels upregulation, inflammatory transcripts upregulation, neuromuscular junction instability and axonal damage.
RESUMO
Several studies documented the key role of oxidative stress and abnormal production of reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies (MDs). The sources of ROS, however, are still controversial as well as their major molecular targets. This study investigated whether ROS produced in mitochondria by monoamine oxidase (MAO) contributes to MD pathogenesis. Pargyline, an MAO inhibitor, reduced ROS accumulation along with a beneficial effect on the dystrophic phenotype of Col6a1(-/-) mice, a model of Bethlem myopathy and Ullrich congenital MD, and mdx mice, a model of Duchenne MD. Based on our previous observations on oxidative damage of myofibrillar proteins in heart failure, we hypothesized that MAO-dependent ROS might impair contractile function in dystrophic muscles. Indeed, oxidation of myofibrillar proteins, as probed by formation of disulphide cross-bridges in tropomyosin, was detected in both Col6a1(-/-) and mdx muscles. Notably, pargyline significantly reduced myofiber apoptosis and ameliorated muscle strength in Col6a1(-/-) mice. This study demonstrates a novel and determinant role of MAO in MDs, adding evidence of the pivotal role of mitochondria and suggesting a therapeutic potential for MAO inhibition.
Assuntos
Monoaminoxidase/metabolismo , Distrofia Muscular Animal/patologia , Miofibrilas/patologia , Estresse Oxidativo , Animais , Colágeno Tipo VI/genética , Colágeno Tipo VI/fisiologia , Camundongos , Camundongos Knockout , FenótipoRESUMO
INTRODUCTION: Glucocorticoids are the only drugs available for the treatment of Duchenne muscular dystrophy (DMD), but it is unclear whether their efficacy is dependent on their anti-inflammatory activity. METHODS: To address this issue, mdx mice were treated daily with methylprednisolone and non-steroidal anti-inflammatory drugs (NSAIDs: aspirin, ibuprofen, parecoxib). RESULTS: NSAID treatment was effective in ameliorating muscle morphology and reducing macrophage infiltration and necrosis. The percentage of regenerating myofibers was not modified by the treatments. The drugs were effective in reducing COX-2 expression and inflammatory cytokines, but they did not affect utrophin levels. The effects of the treatments on contractile performance were analyzed. Isometric tension did not differ in treated and untreated muscle, but the resistance to fatigue was decreased by treatment with methylprednisolone and aspirin. CONCLUSIONS: NSAIDs have a beneficial effect on mdx muscle morphology, pointing to a crucial role of inflammation in the progression of DMD.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Mediadores da Inflamação/fisiologia , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/patologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Diafragma/efeitos dos fármacos , Diafragma/patologia , Diafragma/fisiologia , Progressão da Doença , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Resultado do TratamentoRESUMO
RATIONALE: Chronic atrial fibrillation (cAF) is associated with atrial contractile dysfunction. Sarcomere remodeling may contribute to this contractile disorder. OBJECTIVE: Here, we use single atrial myofibrils and fast solution switching techniques to directly investigate the impact of cAF on myofilament mechanical function eliminating changes induced by the arrhythmia in atrial myocytes membranes and extracellular components. Remodeling of sarcomere proteins potentially related to the observed mechanical changes is also investigated. METHODS AND RESULTS: Myofibrils were isolated from atrial samples of 15 patients in sinus rhythm and 16 patients with cAF. Active tension changes following fast increase and decrease in [Ca(2+)] and the sarcomere length-passive tension relation were determined in the 2 groups of myofibrils. Compared to sinus rhythm myofibrils, cAF myofibrils showed (1) a reduction in maximum tension and in the rates of tension activation and relaxation; (2) an increase in myofilament Ca(2+) sensitivity; (3) a reduction in myofibril passive tension. The slow beta-myosin heavy chain isoform and the more compliant titin isoform N2BA were up regulated in cAF myofibrils. Phosphorylation of multiple myofilament proteins was increased in cAF as compared to sinus rhythm atrial myocardium. CONCLUSIONS: Alterations in active and passive tension generation at the sarcomere level, explained by translational and post-translational changes of multiple myofilament proteins, are part of the contractile dysfunction of human cAF and may contribute to the self-perpetuation of the arrhythmia and the development of atrial dilatation.
Assuntos
Fibrilação Atrial/fisiopatologia , Miocárdio , Miofibrilas/fisiologia , Idoso , Doença Crônica , Feminino , Átrios do Coração/fisiopatologia , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Miocárdio/patologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Miofibrilas/patologiaRESUMO
Genetic background may partly explain differences in muscle responses to internal or external stimuli. Muscle disuse involves various degrees of skeletal muscle atrophy due to inactivity and mechanical unloading. Whether and to which extent genetic background impacts disuse atrophy and retraining in individuals of different ages are currently unclear. Here, we provide a brief overview of relevant literature on the contribution of genetics to muscle disuse, retraining, and aging, and offer a perspective on unanswered questions on the subject that may open new venues for research.
Assuntos
Músculo Esquelético , Atrofia Muscular , Envelhecimento/genética , Humanos , Músculo Esquelético/patologia , Atrofia Muscular/genética , Atrofia Muscular/patologiaRESUMO
Obesity is a complex condition characterized by abnormal and excessive fat accumulation, resulting in an increased risk for severe health problems. Skeletal muscles play a major role in movement and fat catabolism, but the insulin resistance that comes with obesity makes it difficult to fulfill these tasks. In this study, we analyse two types of training protocols, moderate intensity continuous training (MICT) versus high intensity interval training (HIIT), in a cohort of obese subjects to establish which muscle adaptations favour fat consumption in response to exercise. Mitochondria play a role in fat oxidation. We found protein upregulation of mitochondrial biomarkers, TOMM20 and Cox-4, in HIIT but not in MICT, without detecting any shifts in fibre composition phenotype of the vastus lateralis in both training groups. Interestingly, both MICT and HIIT protocols showed increased protein levels of perilipin PLIN2, which is involved in the delivery and consumption of fats. HIIT also augmented perilipin PLIN5. Perilipins are involved in fat storage in skeletal muscles and their upregulation, along with the analysis of circulatory lipid profiles reported in the present study, suggest important adaptations induced by the two types of training protocols that favour fat consumption and weight loss in obese subjects.
RESUMO
Astronauts experience dramatic loss of muscle mass, decreased strength, and insulin resistance, despite performing daily intense physical exercise that would lead to muscle growth on Earth. Partially mimicking spaceflight, prolonged bed rest causes muscle atrophy, loss of force, and glucose intolerance. To unravel the underlying mechanisms, we employed highly sensitive single fiber proteomics to detail the molecular remodeling caused by unloading and inactivity during bed rest and changes of the muscle proteome of astronauts before and after a mission on the International Space Station. Muscle focal adhesions, involved in fiber-matrix interaction and insulin receptor stabilization, are prominently downregulated in both bed rest and spaceflight and restored upon reloading. Pathways of antioxidant response increased strongly in slow but not in fast muscle fibers. Unloading alone upregulated markers of neuromuscular damage and the pathway controlling EIF5A hypusination. These proteomic signatures of mechanical unloading in muscle fiber subtypes contribute to disentangle the effect of microgravity from the pleiotropic challenges of spaceflight.