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Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations to the dystrophin gene, resulting in deficiency of dystrophin protein, loss of myofiber integrity in skeletal and cardiac muscle, and eventual cell death and replacement with fibrotic tissue. Pathologic cardiac manifestations occur in nearly every DMD patient, with the development of cardiomyopathy-the leading cause of death-inevitable by adulthood. As early cardiac abnormalities are difficult to detect, timely diagnosis and appropriate treatment modalities remain a challenge. There is no cure for DMD; treatment is aimed at delaying disease progression and alleviating symptoms. A comprehensive understanding of the pathophysiological mechanisms is crucial to the development of targeted treatments. While established hypotheses of underlying mechanisms include sarcolemmal weakening, upregulation of pro-inflammatory cytokines, and perturbed ion homeostasis, mitochondrial dysfunction is thought to be a potential key contributor. Several experimental compounds targeting the skeletal muscle pathology of DMD are in development, but the effects of such agents on cardiac function remain unclear. The synergistic integration of small molecule- and gene-target-based drugs with metabolic-, immune-, or ion balance-enhancing compounds into a combinatorial therapy offers potential for treating dystrophin deficiency-induced cardiomyopathy, making it crucial to understand the underlying mechanisms driving the disorder.
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Cardiomiopatias , Mitocôndrias , Distrofia Muscular de Duchenne , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/patologia , Humanos , Cardiomiopatias/terapia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiomiopatias/etiologia , Animais , Mitocôndrias/metabolismo , Distrofina/metabolismo , Distrofina/genética , Distrofina/deficiênciaRESUMO
Duchenne muscular dystrophy (DMD) is caused by genetic mutations in the cytoskeletal-sarcolemmal anchor protein dystrophin. Repeated cycles of sarcolemmal tearing and repair lead to a variety of secondary cellular and physiological stressors that are thought to contribute to weakness, atrophy, and fibrosis. Collectively, these stressors can contribute to a pro-inflammatory milieu in locomotor, cardiac, and respiratory muscles. Given the many unwanted side effects that accompany current anti-inflammatory steroid-based approaches for treating DMD (e.g., glucocorticoids), there is a need to develop new therapies that address inflammation and other cellular dysfunctions. Adiponectin receptor (AdipoR) agonists, which stimulate AdipoR1 and R2 isoforms on various cell types, have emerged as therapeutic candidates for DMD due to their anti-inflammatory, anti-fibrotic, and pro-myogenic properties in pre-clinical human and rodent DMD models. Although these molecules represent a new direction for therapeutic intervention, the mechanisms through which they elicit their beneficial effects are not yet fully understood, and DMD-specific data is limited. The overarching goal of this review is to investigate how adiponectin signaling may ameliorate pathology associated with dystrophin deficiency through inflammatory-dependent and -independent mechanisms and to determine if current data supports their future progression to clinical trials.
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Muscle atrophy and weakness are prevalent features of cancer. Although extensive research has characterized skeletal muscle wasting in cancer cachexia, limited studies have investigated how cardiac structure and function are affected by therapy-naive cancer. Here, the authors used orthotopic, syngeneic models of epithelial ovarian cancer and pancreatic ductal adenocarcinoma, and a patient-derived pancreatic xenograft model, to define the impacts of malignancy on cardiac structure, function, and metabolism. Tumor-bearing mice develop cardiac atrophy and intrinsic systolic and diastolic dysfunction, with arterial hypotension and exercise intolerance. In hearts of ovarian tumor-bearing mice, fatty acid-supported mitochondrial respiration decreased, and carbohydrate-supported respiration increased-showcasing a substrate shift in cardiac metabolism that is characteristic of heart failure. Epithelial ovarian cancer decreased cytoskeletal and cardioprotective gene expression, which was paralleled by down-regulation of transcription factors that regulate cardiomyocyte size and function. Patient-derived pancreatic xenograft tumor-bearing mice show altered myosin heavy chain isoform expression-also a molecular phenotype of heart failure. Markers of autophagy and ubiquitin-proteasome system were upregulated by cancer, providing evidence of catabolic signaling that promotes cardiac wasting. Together, the authors cross-validate with two cancer types, evidence of the structural, functional, and metabolic cancer-induced cardiomyopathy, thus providing translational evidence that could impact future medical management strategies for improved cancer recovery in patients.
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AIMS: Type 1 diabetes has been associated with mitochondrial dysfunction. However, the mechanism of this dysfunction in adults remains unclear. METHODS: A secondary analysis was conducted using data from several clinical trials measuring in-vivo and ex-vivo mitochondrial function in adults with type 1 diabetes (n = 34, age 38.8 ± 14.6 years) and similarly aged controls (n = 59, age 44.6 ± 13.9 years). In-vivo mitochondrial function was assessed before, during, and after isometric exercise with 31phosphorous magnetic resonance spectroscopy. High resolution respirometry of vastus lateralis muscle tissue was used to assess ex-vivo measures. RESULTS: In-vivo data showed higher rates of anaerobic glycolysis (p = 0.013), and a lower maximal mitochondrial oxidative capacity (p = 0.012) and mitochondrial efficiency (p = 0.024) in adults with type 1 diabetes. After adjustment for age and percent body fat maximal mitochondrial capacity (p = 0.014) continued to be lower and anaerobic glycolysis higher (p = 0.040) in adults with type 1 diabetes. Ex-vivo data did not demonstrate significant differences between the two groups. CONCLUSIONS: The in-vivo analysis demonstrates that adults with type 1 diabetes have mitochondrial dysfunction. This builds on previous research showing in-vivo mitochondrial dysfunction in youths with type 1 diabetes and suggests that defects in substrate or oxygen delivery may play a role in in-vivo dysfunction.
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Diabetes Mellitus Tipo 1 , Mitocôndrias Musculares , Humanos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Glicólise/fisiologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/fisiopatologia , Doenças Mitocondriais/complicações , Estudos de Casos e Controles , Espectroscopia de Ressonância Magnética , Adulto Jovem , Exercício Físico/fisiologiaRESUMO
Altered mitochondrial structure and function are implicated in the functional decline of skeletal muscle. Numerous cytoskeletal proteins are known to affect mitochondrial homeostasis, but this complex network is still being unraveled. Here, we investigated mitochondrial alterations in mice lacking the cytoskeletal adapter protein, XIN (XIN-/-). XIN-/- and wild-type littermate male and female mice were fed a chow or high-fat diet (HFD; 60% kcal fat) for 8 weeks before analyses of their skeletal muscles was conducted. Immuno-electron microscopy (EM) and immunofluorescence staining revealed XIN in the mitochondria and peri-mitochondrial areas, as well as the myoplasm. Intermyofibrillar mitochondria in chow-fed XIN-/- mice were notably different from wild-type (large, and/or swollen in appearance). Succinate Dehydrogenase and Cytochrome Oxidase IV staining indicated greater evidence of mitochondrial enzyme activity in XIN-/- mice. No difference in body mass gains or glucose handling was observed between cohorts with HFD. However, EM revealed significantly greater mitochondrial density with evident structural abnormalities (swelling, reduced cristae density) in XIN-/- mice. Absolute Complex I and II-supported respiration was not different between groups, but relative to mitochondrial density, was significantly lower in XIN-/-. These results provide the first evidence for a role of XIN in maintaining mitochondrial morphology and function.
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OBJECTIVES: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice. METHODS: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm â¼45, â¼75 and â¼90 days after EOC injection. RESULTS: Primary ovarian tumour sizes were progressively larger at each time point while severe metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-severe-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and severe metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling. CONCLUSIONS: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes severe metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-severe-metastatic weakness during EOC in addition to therapies targeting cachexia.
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Caquexia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Mitocôndrias , Debilidade Muscular , Neoplasias Ovarianas , Animais , Caquexia/metabolismo , Caquexia/etiologia , Caquexia/patologia , Feminino , Camundongos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/complicações , Debilidade Muscular/metabolismo , Debilidade Muscular/etiologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Metástase Neoplásica , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular TumoralRESUMO
INTRODUCTION: Individuals with type 1 diabetes (T1D) experience a complex set of alterations to skeletal muscle metabolic, neuromuscular, and vascular health; collectively referred to as diabetic myopathy. While the full scope of diabetic myopathy is still being elucidated, evidence suggests that even when individuals with T1D are physically active, indices of myopathy still exist. As such, there is a question if adherence to current physical activity guidelines elicits improvements in skeletal muscle health indices similarly between individuals with and without T1D. The objectives of this trial are to: 1) compare baseline differences in skeletal muscle health between adults with and without T1D, 2) examine the association between participation in a home-based exercise program, detraining, and retraining, with changes in skeletal muscle health, and 3) examine the roles of age and sex on these associations. METHODS AND ANALYSIS: This will be a prospective interventional trial. Younger (18-30 years) and older (45-65 years) males and females with T1D and matched individuals without T1D will engage in a four-phase, 18-week study sequentially consisting of a one-week lead-in period, 12-week exercise training program, one-week detraining period, and four-week retraining period. The exercise program will consist of aerobic and resistance exercise based on current guidelines set by Diabetes Canada. Metabolic, neuromuscular, and vascular outcome measures will be assessed four times: at baseline, post-exercise program, post-detraining, and post-retraining. Differences in baseline metrics between those with and without T1D will be examined with independent sample t-tests, and with two-way analyses of variance for age- and sex-stratified analyses. Changes across the duration of the study will be examined using mixed-model analyses. DISSEMINATION: Findings from this research will be shared locally and internationally with research participants, clinicians, diabetes educators, and patient advocacy organizations via in-person presentations, social media, and scientific fora. TRIAL REGISTRATION NUMBER: NCT05740514.
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Diabetes Mellitus Tipo 1 , Exercício Físico , Músculo Esquelético , Humanos , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/fisiopatologia , Masculino , Feminino , Músculo Esquelético/fisiopatologia , Adulto , Pessoa de Meia-Idade , Estudos Prospectivos , Adolescente , Idoso , Exercício Físico/fisiologia , Adulto Jovem , Terapia por Exercício/métodosRESUMO
Objectives: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice. Methods: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ~45, ~75 and ~90 days after EOC injection. Results: Primary ovarian tumour sizes were progressively larger at each time point while robust metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling. Conclusion: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-metastatic weakness during EOC in addition to therapies targeting cachexia.
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Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analog, ALY688-SR, remodels the diaphragm of murine model of DMD on DBA background (D2.mdx) mice treated from days 7-28 of age during early stages of disease. ALY688-SR also lowered interleukin-6 (IL-6) mRNA but increased IL-6 and transforming growth factor-ß1 (TGF-ß1) protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H2O2 emission. Treatment also attenuated fibrosis, fiber type-specific atrophy, and in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling, and force-generating properties during the very early stages of disease progression in murine model of DMD on DBA background (D2.mdx) mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR in young D2.mdx mice partially prevents fibrosis and fiber type-specific atrophy and lowers force production in the more disease-apparent diaphragm in relation to lower mitochondrial redox stress and heterogeneous responses in certain inflammatory markers. These diverse muscle responses to adiponectin receptor agonism in early stages of DMD serve as a foundation for further mechanistic investigations.NEW & NOTEWORTHY There are limited therapies for the treatment of Duchenne muscular dystrophy. As fibrosis involves an accumulation of collagen that replaces muscle fibers, antifibrotics may help preserve muscle function. We report that the novel adiponectin receptor agonist ALY688-SR prevents fibrosis in the diaphragm of D2.mdx mice with short-term treatment early in disease progression. These responses were related to altered inflammation and mitochondrial functions and serve as a foundation for the development of this class of therapy.
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Distrofia Muscular de Duchenne , Animais , Camundongos , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Adiponectina/genética , Modelos Animais de Doenças , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , Peróxido de Hidrogênio/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Camundongos Endogâmicos DBA , Músculo Esquelético/metabolismo , Diafragma/metabolismo , Fibrose , Inflamação/metabolismo , Progressão da Doença , Atrofia/metabolismo , Atrofia/patologiaRESUMO
NEW FINDINGS: What is the central question of this study? Can adiponectin receptor agonism improve recognition memory in a mouse model of Duchenne muscular dystrophy? What is the main finding and its importance? Short-term treatment with the new adiponectin receptor agonist ALY688 improves recognition memory in D2.mdx mice. This finding suggests that further investigation into adiponectin receptor agonism is warranted, given that there remains an unmet need for clinical approaches to treat this cognitive dysfunction in people with Duchenne muscular dystrophy. ABSTRACT: Memory impairments have been well documented in people with Duchenne muscular dystrophy (DMD). However, the underlying mechanisms are poorly understood, and there is an unmet need to develop new therapies to treat this condition. Using a novel object recognition test, we show that recognition memory impairments in D2.mdx mice are completely prevented by daily treatment with the new adiponectin receptor agonist ALY688 from day 7 to 28 of age. In comparison to age-matched wild-type mice, untreated D2.mdx mice demonstrated lower hippocampal mitochondrial respiration (carbohydrate substrate), greater serum interleukin-6 cytokine content and greater hippocampal total tau and Raptor protein contents. Each of these measures was partly or fully preserved after treatment with ALY688. Collectively, these results indicate that adiponectin receptor agonism improves recognition memory in young D2.mdx mice.
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Distrofia Muscular de Duchenne , Animais , Camundongos , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Camundongos Endogâmicos mdx , Receptores de Adiponectina/metabolismo , Receptores de Adiponectina/uso terapêutico , Adiponectina/metabolismo , Respiração , Modelos Animais de Doenças , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Músculo Esquelético/metabolismoRESUMO
Duchenne muscular dystrophy (DMD) is associated with distinct mitochondrial stress responses. Here, we aimed to determine whether the prospective mitochondrial-enhancing compound Olesoxime, prevents early-stage mitochondrial stress in limb and respiratory muscle from D2.mdx mice using a proof-of-concept short-term regimen spanning 10-28 days of age. As mitochondrial-cytoplasmic energy transfer occurs via ATP- or phosphocreatine-dependent phosphate shuttling, we assessed bioenergetics with or without creatine in vitro. We observed that disruptions in Complex I-supported respiration and mH2O2 emission in D2.mdx quadriceps and diaphragm were amplified by creatine demonstrating mitochondrial creatine insensitivity manifests ubiquitously and early in this model. Olesoxime selectively rescued or maintained creatine sensitivity in both muscles, independent of the abundance of respiration-related mitochondrial proteins or mitochondrial creatine kinase cysteine oxidation in quadriceps. Mitochondrial calcium retention capacity and glutathione were altered in a muscle-specific manner in D2.mdx but were generally unchanged by Olesoxime. Treatment reduced serum creatine kinase (muscle damage) and preserved cage hang-time, microCT-based volumes of lean compartments including whole body, hindlimb and bone, recovery of diaphragm force after fatigue, and cross-sectional area of diaphragm type IIX fiber, but reduced type I fibers in quadriceps. Grip strength, voluntary wheel-running and fibrosis were unaltered by Olesoxime. In summary, locomotor and respiratory muscle mitochondrial creatine sensitivities are lost during early stages in D2.mdx mice but are preserved by short-term treatment with Olesoxime in association with specific indices of muscle quality suggesting early myopathy in this model is at least partially attributed to mitochondrial stress.
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Distrofia Muscular de Duchenne , Animais , Camundongos , Distrofia Muscular de Duchenne/metabolismo , Camundongos Endogâmicos mdx , Creatina/metabolismo , Camundongos Endogâmicos C57BL , Estudos Prospectivos , Diafragma/metabolismo , Músculo Esquelético , Modelos Animais de DoençasRESUMO
Exercise is one of the only nonpharmacological remedies known to counteract genetic and chronic diseases by enhancing health and improving life span. Although the many benefits of regular physical activity have been recognized for some time, the intricate and complex signaling systems triggered at the onset of exercise have only recently begun to be uncovered. Exercising muscles initiate a coordinated, multisystemic, metabolic rewiring, which is communicated to distant organs by various molecular mediators. The field of exercise research has been expanding beyond the musculoskeletal system, with interest from industry to provide realistic models and exercise mimetics that evoke a whole body rejuvenation response. The 18th International Biochemistry of Exercise conference took place in Toronto, Canada, from May 25 to May 28, 2022, with more than 400 attendees. Here, we provide an overview of the most cutting-edge exercise-related research presented by 66 speakers, focusing on new developments in topics ranging from molecular and cellular mechanisms of exercise adaptations to exercise therapy and management of disease and aging. We also describe how the manipulation of these signaling pathways can uncover therapeutic avenues for improving human health and quality of life.
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Exercício Físico , Qualidade de Vida , Humanos , Exercício Físico/fisiologia , Adaptação Fisiológica , Envelhecimento/fisiologia , Terapia por Exercício , Músculo Esquelético/metabolismoRESUMO
Compared to age-matched men, pre-menopausal women show greater resilience against cardiovascular disease (CVD), hepatic steatosis, diabetes and obesity - findings that are widely attributed to oestrogen. However, meta-analysis data suggest that current use of oral combined contraceptives (OC) is a risk factor for myocardial infarction, and OC use further compounds with metabolic disease risk factors to increase CVD susceptibility. While mitochondrial function in tissues such as the liver and skeletal muscle is an emerging mechanism by which oestrogen may confer its protection, effects of OC use on mitochondria and metabolism in the context of disease risk remain unexplored. To answer this question, female C57Bl/6J mice were fed a high fat diet and treated with vehicle or OCs for 3, 12 or 20 weeks (n = 6 to 12 per group) at a dose and ratio that mimic the human condition of cycle cessation in the low oestrogen, high progesterone stage. Liver and skeletal muscle mitochondrial function (respiratory capacity, H2 O2 , coupling) was measured along with clinical outcomes of cardiometabolic disease such as obesity, glucose tolerance, hepatic steatosis and aortic atherosclerosis. The main findings indicate that regardless of treatment duration, OCs robustly increase hepatic mitochondrial H2 O2 levels, likely due to diminished antioxidant capacity, but have no impact on muscle mitochondrial H2 O2 . Furthermore, OC-treated mice had lower adiposity and hepatic triglyceride content compared to control mice despite reduced wheel running, spontaneous physical activity and total energy expenditure. Together, these studies describe tissue-specific effects of OC use on mitochondria as well as variable impacts on markers of metabolic disease susceptibility. KEY POINTS: Oestrogen loss in women increases risk for cardiometabolic diseases, a link that has been partially attributed to negative impacts on mitochondria and energy metabolism. To study the effect of oral combined contraceptives (OCs) on hepatic and skeletal muscle mitochondria and whole-body energy metabolism, we used an animal model of OCs which mimics the human condition of cessation of hormonal cycling in the low oestrogen, high progesterone state. OC-treated mice have increased hepatic mitochondrial oxidative stress and decreased physical activity and energy expenditure, despite displaying lower adiposity and liver fat at this time point. These pre-clinical data reveal tissue-specific effects of OCs that likely underlie the clinical findings of increased cardiometabolic disease in women who use OCs compared to non-users, when matched for obesity.
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Anticoncepcionais Orais , Infarto do Miocárdio , Feminino , Humanos , Camundongos , Animais , Espécies Reativas de Oxigênio , Progesterona , Atividade Motora , Fígado , Estrogênios/farmacologia , Mitocôndrias , ObesidadeRESUMO
Mitochondrial stress may be a secondary contributor to muscle weakness in inherited muscular dystrophies. Duchenne muscular dystrophy has received the majority of attention, whereby most discoveries suggest mitochondrial ATP synthesis may be reduced. However, not all studies support this finding. Furthermore, some studies have reported increased mitochondrial reactive oxygen species and propensity for permeability transition pore formation as an inducer of apoptosis, although divergent findings have also been described. A closer examination of the literature suggests the degree and direction of mitochondrial stress responses may depend on the progression of the disease, the muscle type examined, the mouse model used with regard to preclinical research, the precise metabolic pathways in consideration, and in some cases, the in vitro technique used to assess a given mitochondrial bioenergetic function. One intent of this review is to provide careful considerations for future experimental designs to resolve the heterogeneous nature of mitochondrial stress during the progression of Duchenne muscular dystrophy. Such considerations have implications for other muscular dystrophies as well which are addressed briefly herein. A renewed perspective of the term "mitochondrial dysfunction" is presented whereby stress responses might be re-explored in future investigations as direct contributors to myopathy versus an adaptive "reprogramming" intended to maintain homeostasis in the face of disease stressors themselves. In so doing, the prospective development of mitochondrial enhancement therapies can be driven by advances in perspectives as much as experimental approaches when resolving the precise relationships between mitochondrial remodeling and muscle weakness in Duchenne and, indeed, other muscular dystrophies.
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Distrofia Muscular de Duchenne , Animais , Camundongos , Mitocôndrias/metabolismo , Debilidade Muscular/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Estudos ProspectivosRESUMO
High-intensity interval training (HIIT) generates profound metabolic adaptations in skeletal muscle. These responses mirror performance improvements but follow a nonlinear pattern comprised of an initial fast phase followed by a gradual plateau effect. The complete time-dependent molecular sequelae that regulates this plateau effect remains unknown. We hypothesize that the plateau effect during HIIT is restricted to specific pathways with communal upstream transcriptional regulation. To investigate this, 11 healthy men performed nine sessions of HIIT [10 × 4 min of cycling at 91% of maximal heart rate (HRmax)] over a 3-wk period. Before and 3 h after the 1st and 9th exercise bout, skeletal muscle biopsies were obtained, and RNA sequencing was performed. Almost 2,000 genes across 84 pathways were differentially expressed in response to a single HIIT session. The overall transcriptional response to acute exercise was strikingly similar at 3 wk, 83% (n = 1,650) of the genes regulated after the 1st bout of exercise were similarly regulated by the 9th bout, albeit with a smaller effect size, and the response attenuated to on average 70% of the 1st bout. The attenuation differed substantially between pathways and was especially pronounced for glycolysis and cellular adhesion compared to, e.g., MAPK and vascular endothelial growth factor (VEGF)-A signaling. The attenuation was driven by a combination of changes in steady-state expression and specific transcriptional regulation. Given that the exercise intensity was progressively increased, and the attenuation was pathway-specific, we suggest that moderation of muscular adaptation after a period of training stems from targeted regulation rather than a diminished exercise stimulus.NEW & NOTEWORTHY This is the first study to address the phenomena of attenuation of the acute exercise response on a global genomic scale with a focus on underlying regulatory machinery and it is, to the best of our knowledge, the first study conducted in humans was exercise-induced regulation of different canonical pathways and transcription factors are contrasted with regards to attenuation after a period with regular exercise training. These results provide evidence for a pathway-specific regulated augmentation of the response to acute exercise over time that tracks with the successive adaptation on the systemic level.
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Treinamento Intervalado de Alta Intensidade , Subunidade alfa do Fator 1 Induzível por Hipóxia , Adaptação Fisiológica/fisiologia , Exercício Físico/fisiologia , Treinamento Intervalado de Alta Intensidade/métodos , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Músculo Esquelético/fisiologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
We investigated the effects of a novel multi-ingredient supplement comprised of polyphenol antioxidants and compounds known to facilitate mitochondrial function and metabolic enhancement (ME) in a mouse model of obesity. In this study, 6-week-old male C57/BL6J mice were placed on a high-fat diet (HFD; ~60% fat) for 6 weeks, with subsequent allocation into experimentalgroups for 4 weeks: HFD control, HFD + ME10 (10 components), HFD + ME7 (7 components), HFD + ME10 + EX, HFD + EX (where '+EX' animals exercised 3 days/week), and chow-fed control. After the intervention, HFD control animals had significantly greater body weight and fat mass. Despite the continuation of HFD, animals supplemented with multi-ingredient ME or who performed exercise training showed an attenuation of fat mass and preservation of lean body mass, which was further enhanced when combined (ME+EX). ME supplementation stimulated the upregulation of white and brown adipose tissue mRNA transcripts associated with mitochondrial biogenesis, browning, fatty acid transport, and fat metabolism. In WAT depots, this was mirrored by mitochodrial oxidative phosphorylation (OXPHOS) protein expression, and increased in vivo fat oxidation measured via CLAMS. ME supplementation also decreased systemic and local inflammation markers. Herein, we demonstrated that novel multi-ingredient nutritional supplements induced significant fat loss independent of physical activity while preserving muscle mass in obese mice. Mechanistically, these MEs appear to act by inducing a browning program in white adipose tissue and decreasing other pathophysiological impairments associated with obesity, including mitochondrial respiration alterations induced by HFD.
Assuntos
Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Dieta Hiperlipídica , Suplementos Nutricionais , Comportamento Alimentar , Aumento de Peso/fisiologia , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Circulação Sanguínea , Respiração Celular , Epididimo/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Biogênese de Organelas , Oxirredução , Fosforilação Oxidativa , Fosforilação , Condicionamento Físico Animal , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Superóxido Dismutase/metabolismo , Regulação para Cima , Redução de PesoRESUMO
Accumulating evidence now shows that supplemental antioxidants including vitamin C, vitamin E and N-Acetylcysteine consumption can suppress adaptations to endurance-type exercise by attenuating reactive oxygen and nitrogen species (RONS) formation within skeletal muscle. This emerging evidence points to the importance of pro-oxidation as an important stimulus for endurance-training adaptations, including mitochondrial biogenesis, endogenous antioxidant production, insulin signalling, angiogenesis and growth factor signaling. Although sustained oxidative distress is associated with many chronic diseases, athletes have, on average, elevated levels of certain endogenous antioxidants to maintain redox homeostasis. As a result, trained athletes may have a better capacity to buffer oxidants during and after exercise, resulting in a reduced oxidative eustress stimulus for adaptations. Thus, higher levels of RONS input and exercise-induced oxidative stress may benefit athletes in the pursuit of continuous endurance training redox adaptations. This review addresses why athletes should be looking to enhance exercise-induced oxidative stress and how it can be accomplished. Methods covered include high-intensity interval training, hyperthermia and heat stress, dietary antioxidant restriction and modified antioxidant timing, dietary antioxidants and polyphenols as adjuncts to exercise, and vitamin C as a pro-oxidant.
Assuntos
Treino Aeróbico , Adaptação Fisiológica , Antioxidantes , Humanos , Músculo Esquelético , Espécies Reativas de OxigênioRESUMO
AIMS/HYPOTHESIS: This study interrogated mitochondrial respiratory function and content in skeletal muscle biopsies of healthy adults between 30 and 72 years old with and without uncomplicated type 1 diabetes. METHODS: Participants (12 women/nine men) with type 1 diabetes (48 ± 11 years of age), without overt complications, were matched for age, sex, BMI and level of physical activity to participants without diabetes (control participants) (49 ± 12 years of age). Participants underwent a Bergström biopsy of the vastus lateralis to assess mitochondrial respiratory function using high-resolution respirometry and citrate synthase activity. Electron microscopy was used to quantify mitochondrial content and cristae (pixel) density. RESULTS: Mean mitochondrial area density was 27% lower (p = 0.006) in participants with type 1 diabetes compared with control participants. This was largely due to smaller mitochondrial fragments in women with type 1 diabetes (-18%, p = 0.057), as opposed to a decrease in the total number of mitochondrial fragments in men with diabetes (-28%, p = 0.130). Mitochondrial respiratory measures, whether estimated per milligram of tissue (i.e. mass-specific) or normalised to area density (i.e. intrinsic mitochondrial function), differed between cohorts, and demonstrated sexual dimorphism. Mass-specific mitochondrial oxidative phosphorylation (OXPHOS) capacity with the substrates for complex I and complex II (CI + II) was significantly lower (-24%, p = 0.033) in women with type 1 diabetes compared with control participants, whereas mass-specific OXPHOS capacities with substrates for complex I only (pyruvate [CI pyr] or glutamate [CI glu]) or complex II only (succinate [CII succ]) were not different (p > 0.404). No statistical differences (p > 0.397) were found in mass-specific OXPHOS capacity in men with type 1 diabetes compared with control participants despite a 42% non-significant increase in CI glu OXPHOS capacity (p = 0.218). In contrast, intrinsic CI + II OXPHOS capacity was not different in women with type 1 diabetes (+5%, p = 0.378), whereas in men with type 1 diabetes it was 25% higher (p = 0.163) compared with control participants. Men with type 1 diabetes also demonstrated higher intrinsic OXPHOS capacity for CI pyr (+50%, p = 0.159), CI glu (+88%, p = 0.033) and CII succ (+28%, p = 0.123), as well as higher intrinsic respiratory rates with low (more physiological) concentrations of either ADP, pyruvate, glutamate or succinate (p < 0.012). Women with type 1 diabetes had higher (p < 0.003) intrinsic respiratory rates with low concentrations of succinate only. Calculated aerobic fitness (Physical Working Capacity Test [PWC130]) showed a strong relationship with mitochondrial respiratory function and content in the type 1 diabetes cohort. CONCLUSIONS/INTERPRETATION: In middle- to older-aged adults with uncomplicated type 1 diabetes, we conclude that skeletal muscle mitochondria differentially adapt to type 1 diabetes and demonstrate sexual dimorphism. Importantly, these cellular alterations were significantly associated with our metric of aerobic fitness (PWC130) and preceded notable impairments in skeletal mass and strength.
Assuntos
Respiração Celular/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Adulto , Idoso , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação Oxidativa , Consumo de Oxigênio/fisiologia , Mecânica RespiratóriaRESUMO
Cellular senescence is the irreversible arrest of normally dividing cells and is driven by cell cycle inhibitory proteins such as p16, p21, and p53. When cells enter senescence, they secrete a host of proinflammatory factors known as the senescence-associated secretory phenotype, which has deleterious effects on surrounding cells and tissues. Little is known of the role of senescence in Duchenne muscular dystrophy (DMD), the fatal X-linked neuromuscular disorder typified by chronic inflammation, extracellular matrix remodeling, and a progressive loss in muscle mass and function. Here, we demonstrate using C57-mdx (8-wk-old) and D2-mdx (4-wk-old and 8-wk-old) mice, two mouse models of DMD, that cells displaying canonical markers of senescence are found within the skeletal muscle. Eight-week-old D2-mdx mice, which display severe muscle pathology, had greater numbers of senescent cells associated with areas of inflammation, which were mostly Cdkn1a-positive macrophages, whereas in C57-mdx muscle, senescent populations were endothelial cells and macrophages localized to newly regenerated myofibers. Interestingly, this pattern was similar to cardiotoxin (CTX)-injured wild-type (WT) muscle, which experienced a transient senescent response. Dystrophic muscle demonstrated significant upregulations in senescence pathway genes [Cdkn1a (p21), Cdkn2a (p16INK4A), and Trp53 (p53)], which correlated with the quantity of senescence-associated ß-galactosidase (SA-ß-Gal)-positive cells. These results highlight an underexplored role for cellular senescence in murine dystrophic muscle.