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Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function, which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function, thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia, TIL infiltration and effector function, and mitochondrial content, morphology and function were evaluated. AET reduced tumor growth, improved survival, and decreased tumor hypoxia. An increased CD8 + TIL infiltration, IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively, AET decreases tumor growth partially by increasing CD8 + TIL effector function through an improvement in their mitochondrial content and function., Competing Interests: The authors declare no competing interest., (© 2024 The Authors.)

Immune checkpoint inhibitors (ICIs) show limited success in treating pancreatic ductal adenocarcinoma (PDAC), largely due to immune evasion mechanisms, including downregulating expression of major histocompatibility complex class I (MHC-I). Our retrospective analysis demonstrated that smoking - a state of elevated CO exposure - is correlated with increased MHC I expression in pancreatic tumors. Here we tested our hypothesis that introducing exogenous CO augments the anti-cancer effects of immunotherapy. To evaluate this influence, we created a novel oral delivery system for CO, termed CO-Gas-entrapping materials (GeMs), utilizing Food and Drug Administration Generally Recognized as Safe components. In vitro studies demonstrated that CO exposure increased MHC-I and PD-L1 gene and protein expression in various pancreatic cancer cell lines, as well as enhancing T-cell migration and recruitment. In vivo studies showed increased T-cell infiltration in PDAC allograft tumors treated with the combination therapy as confirmed by flow cytometry and immunohistochemical analysis. Further, CO-GeMs combined with ICIs significantly suppressed tumor growth in multiple PDAC mouse models, including subcutaneous and hepatic metastatic allograft models. These findings suggest that CO enhances immune recognition to potentiate the efficacy of ICIs in PDAC. Thus, our CO-GeMs offer a safe, effective method for systemic CO delivery to treat cancer, representing a promising adjunct to immunotherapy in PDAC and potentially other malignancies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leo Otterbein, Giovanni Traverso, and James Byrne report a relationship with GEM Biosciences that includes: equity or stocks. Leo Otterbein, Giovanni Traverso, Emily Witt, James Byrne have patents pending to University of Iowa, MIT, BIDMC. Equity in Focal Medical Inc. and Teal Bio Inc., unrelated to work herein If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Exercise training reduces the incidence of several cancers, but the mechanisms underlying these effects are not fully understood. Exercise training can affect the spleen function, which controls the hematopoiesis and immune response. Analyzing different cancer models, we identified that 4T1, LLC, and CT26 tumor-bearing mice displayed enlarged spleen (splenomegaly), and exercise training reduced spleen mass toward control levels in two of these models (LLC and CT26). Exercise training also slowed tumor growth in melanoma B16F10, colon tumor 26 (CT26), and Lewis lung carcinoma (LLC) tumor-bearing mice, with minor effects in mammary carcinoma 4T1, MDA-MB-231, and MMTV-PyMT mice. In silico analyses using transcriptome profiles derived from these models revealed that platelet factor 4 (Pf4) is one of the main upregulated genes associated with splenomegaly during cancer progression. To understand whether exercise training would modulate the expression of these genes in the tumor and spleen, we investigated particularly the CT26 model, which displayed splenomegaly and had a clear response to the exercise training effects. RT-qPCR analysis confirmed that trained CT26 tumor-bearing mice had decreased Pf4 mRNA levels in both the tumor and spleen when compared to untrained CT26 tumor-bearing mice. Furthermore, exercise training specifically decreased Pf4 mRNA levels in the CT26 tumor cells. Aspirin treatment did not change tumor growth, splenomegaly, and tumor Pf4 mRNA levels, confirming that exercise decreased non-platelet Pf4 mRNA levels. Finally, tumor Pf4 mRNA levels are deregulated in The Cancer Genome Atlas Program (TCGA) samples and predict survival in multiple cancer types. This highlights the potential therapeutic value of exercise as a complementary approach to cancer treatment and underscores the importance of understanding the exercise-induced transcriptional changes in the spleen for the development of novel cancer therapies., (© 2023. The Author(s).)

Heme is an iron-protoporphyrin complex with an essential physiologic function for all cells, especially for those in which heme is a key prosthetic group of proteins such as hemoglobin, myoglobin, and cytochromes of the mitochondria. However, it is also known that heme can participate in pro-oxidant and pro-inflammatory responses, leading to cytotoxicity in various tissues and organs such as the kidney, brain, heart, liver, and in immune cells. Indeed, heme, released as a result of tissue damage, can stimulate local and remote inflammatory reactions. These can initiate innate immune responses that, if left uncontrolled, can compound primary injuries and promote organ failure. In contrast, a cadre of heme receptors are arrayed on the plasma membrane that is designed either for heme import into the cell, or for the purpose of activating specific signaling pathways. Thus, free heme can serve either as a deleterious molecule, or one that can traffic and initiate highly specific cellular responses that are teleologically important for survival. Herein, we review heme metabolism and signaling pathways, including heme synthesis, degradation, and scavenging. We will focus on trauma and inflammatory diseases, including traumatic brain injury, trauma-related sepsis, cancer, and cardiovascular diseases where current work suggests that heme may be most important.

Tumor hypoxia drives resistance to many cancer therapies, including radiotherapy and chemotherapy. Methods that increase tumor oxygen pressures, such as hyperbaric oxygen therapy and microbubble infusion, are utilized to improve the responses to current standard-of-care therapies. However, key obstacles remain, in particular delivery of oxygen at the appropriate dose and with optimal pharmacokinetics. Toward overcoming these hurdles, gas-entrapping materials (GeMs) that are capable of tunable oxygen release are formulated. It is shown that injection or implantation of these materials into tumors can mitigate tumor hypoxia by delivering oxygen locally and that these GeMs enhance responsiveness to radiation and chemotherapy in multiple tumor types. This paper also demonstrates, by comparing an oxygen (O 2 )-GeM to a sham GeM, that the former generates an antitumorigenic and immunogenic tumor microenvironment in malignant peripheral nerve sheath tumors. Collectively the results indicate that the use of O 2 -GeMs is promising as an adjunctive strategy for the treatment of solid tumors., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Oxygen and carbon dioxide are time honored gases that have direct bearing on almost all life forms, but over the past thirty years, and in large part due to the Nobel Prize Award in Medicine for the elucidation of nitric oxide (NO) as a bioactive gas, the research and medical communities now recognize other gases as critical for survival. In addition to NO, hydrogen sulfide (H 2 S) and carbon monoxide (CO) have emerged as a triumvirate or Trinacrium of gases with analogous importance and that serve important homeostatic functions. Perhaps, one of the most intriguing aspects of these gases is the functional interaction between them, which is intimately linked by the enzyme systems that produce them. Despite the need to better understand NO, H 2 S and CO biology, the notion that these are environmental pollutants remains ever present. For this reason, incorporating the concept of hormesis becomes imperative and must be included in discussions when considering developing new therapeutics that involve these gases. While there is now an enormous literature base for each of these gasotransmitters, we provide here an overview of their respective physiologic roles in the brain., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cancer cachexia is a multifactorial and devastating syndrome characterized by severe skeletal muscle mass loss and dysfunction. As cachexia still has neither a cure nor an effective treatment, better understanding of skeletal muscle plasticity in the context of cancer is of great importance. Although aerobic exercise training (AET) has been shown as an important complementary therapy for chronic diseases and associated comorbidities, the impact of AET on skeletal muscle mass maintenance during cancer progression has not been well documented yet. Here, we show that previous AET induced a protective mechanism against tumor-induced muscle wasting by modulating the Akt/mTORC1 signaling and eukaryotic initiation factors, specifically eIF2-α. Thereafter, it was determined whether the in vivo Akt activation would induce a hypertrophic profile in cachectic muscles. As observed for the first time, Akt-induced hypertrophy was able and sufficient to either prevent or revert cancer cachexia by modulating both Akt/mTORC1 pathway and the eIF-2α activation, and induced a better muscle functionality. These findings provide evidence that skeletal muscle tissue still preserves hypertrophic potential to be stimulated by either AET or gene therapy to counteract cancer cachexia.

Background: Most cancer patients, under active treatment or not, are sedentary, despite increasing scientific and clinical understanding of the benefits of exercise and physical activity, such as improving quality of life, limiting disease symptoms, decreasing cancer recurrence, and increasing overall survival. Studies have shown that both supervised exercise and unsupervised physical activity programs have low adherence and limited long-term benefits among cancer survivors. Therefore, interventions focused on increasing physical activity levels have clinical and psychological relevance. The present study will examine the feasibility and efficacy of an intervention that combines supervised group exercise with active lifestyle recommendations, analyzing its clinical, psychological, physiological, functional, and immunological effects in breast cancer survivors., Methods: Women aged 35-75 years who have completed chemotherapy, radiotherapy, and surgery for breast cancer will be recruited from the Cancer Institute of the State of Sao Paulo (ICESP) and take part in a 16-week, parallel-group, randomized, and controlled trial. They will receive a booklet with recommendations for achieving a physically active lifestyle by increasing overall daily movement and undertaking at least 150 min/week of structured exercise. Then, they will be randomized into two groups: the supervised group will take part in two canoeing group exercise sessions every week, and the unsupervised group will increase their overall physical activity level by any means, such as active commuting, daily activities, or home-based exercise. Primary outcome includes aerobic capacity. Secondary outcomes are physical activity, physical functioning, self-reported quality of life, fatigue, presence of lymphedema, body composition, immune function, adherence to physical activity guidelines, and perceptions of self-image., Discussion: Results should contribute to advance knowledge on the impact of a supervised group exercise intervention to improve aspects related to health, physical functioning, and quality of life in female breast cancer survivors., Trial Registration: Brazilian Registry of Clinical Trials Number: RBR-3fw9xf. Retrospectively Registered on 27 December 2018. Items from the World Health Organization Trial Registration Data Set can be accessed on http://www.ensaiosclinicos.gov.br/rg/RBR-3fw9xf/ ., (© 2021. The Author(s).)

We tested the hypothesis that cancer cachexia progression would induce oxidative post-translational modifications (Ox-PTMs) associated with skeletal muscle wasting, with different responses in muscles with the prevalence of glycolytic and oxidative fibers. We used cysteine-specific isotopic coded affinity tags (OxICAT) and gel-free mass spectrometry analysis to investigate the cysteine Ox-PTMs profile in the proteome of both plantaris (glycolytic) and soleus (oxidative) muscles in tumor-bearing and control rats. Histological analysis revealed muscle atrophy in type II fibers in plantaris muscle, with no changes in plantaris type I fibers and no differences in both soleus type I and II fibers in tumor-bearing rats when compared to healthy controls. Tumor progression altered the Ox-PTMs profile in both plantaris and soleus. However, pathway analysis including the differentially oxidized proteins revealed tricarboxylic acid cycle and oxidative phosphorylation as main affected pathways in plantaris muscle from tumor-bearing rats, while the same analysis did not show main metabolic pathways affected in the soleus muscle. In addition, cancer progression affected several metabolic parameters such as ATP levels and markers of oxidative stress associated with muscle atrophy in plantaris muscle, but not in soleus. However, isolated soleus from tumor-bearing rats had a reduced force production capacity when compared to controls. These novel findings demonstrate that tumor-bearing rats have severe muscle atrophy exclusively in glycolytic fibers. Cancer progression is associated with cysteine Ox-PTMs in the skeletal muscle, but these modifications affect different pathways in a glycolytic muscle compared to an oxidative muscle, indicating that intrinsic muscle oxidative capacity determines the response to cancer cachectic effects., (© 2021 Federation of American Societies for Experimental Biology.)

Aims: We aimed to investigate the impact of cancer cachexia and previous aerobic exercise training (AET) on cardiac function and structure in tumor bearing mice., Main Methods: Colon adenocarcinoma cells 26 (CT26) were subcutaneously injected in BALB/c mice to establish robust cancer cachexia model. AET was performed on a treadmill during 45 days, 60 min/5 days per week. Cardiac function was evaluated by echocardiography and cardiac morphology was assessed by light microscopy. The protein expression levels of mitochondrial complex were analyzed by Western blotting. The mRNA levels of genes related to cardiac remodeling and autophagy were analyzed by quantitative Real-Time PCR., Key Findings: Our data confirms CT26 tumor bearing mice as a well-characterized and robust model of cancer cachexia. CT26 mice exhibited cardiac remodeling and dysfunction characterized by cardiac atrophy and impaired left ventricle ejection fraction paralleled by cardiac necrosis, inflammation and fibrosis. AET partially reversed the left ventricle ejection fraction and led to significant anti-cardiac remodeling effect associated reduced necrosis, inflammation and cardiac collagen deposition in CT26 mice. Reduced TGF-β1 mRNA levels, increased mitochondrial complex IV protein levels and partial recovery of BNIP3 mRNA levels in cardiac tissue were associated with the cardiac effects of AET in CT26 mice. Thus, we suggest AET as a powerful regulator of key pathways involved in cardiac tissue homeostasis in cancer cachexia., Significance: Our study provides a robust model of cancer cachexia, as well as highlights the potential and integrative effects of AET as a preventive strategy for reducing cardiac damage in cancer cachexia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia., Methods: We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats., Results: Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to age-matched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity., Conclusions: These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Disruption of endoplasmic reticulum (ER) homeostasis is a common feature of cardiac diseases. However, the signaling events involved in ER stress-induced cardiac dysfunction are still elusive. Here, we uncovered a mechanism by which disruption of ER homeostasis impairs cardiac contractility., Methods/results: We found that ER stress is associated with activation of JNK and upregulation of BNIP3 in a post-myocardial infarction (MI) model of cardiac dysfunction. Of interest, 4-week treatment of MI rats with the chemical ER chaperone 4-phenylbutyrate (4PBA) prevented both activation of JNK and upregulation of BNIP3, and improved cardiac contractility. We showed that disruption of ER homeostasis by treating adult rat cardiomyocytes in culture with tunicamycin leads to contractile dysfunction through JNK signaling pathway. Upon ER stress JNK upregulates BNIP3 in a FOXO3a-dependent manner. Further supporting a BNIP3 mechanism for ER stress-induced deterioration of cardiac function, siRNA-mediated BNIP3 knockdown mitigated ER stress-induced cardiomyocyte dysfunction by reestablishing sarcoplasmic reticulum Ca 2+ content., Conclusions: Collectively, our data identify JNK-dependent upregulation of BNIP3 as a critical process involved in ER stress-induced cardiomyocyte contractile dysfunction and highlight 4PBA as a potential intervention to counteract ER stress-mediated BNIP3 upregulation in failing hearts., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Increased proteolytic activity has been widely associated with skeletal muscle atrophy. However, elevated proteolysis is also critical for the maintenance of cellular homeostasis by disposing cytotoxic proteins and non-functioning organelles. We recently demonstrated that exercise activates autophagy and re-establishes proteostasis in cardiac diseases. Here, we characterized the impact of exercise on skeletal muscle autophagy and proteostasis in a model of neurogenic myopathy induced by sciatic nerve constriction in rats. Neurogenic myopathy, characterized by progressive atrophy and impaired contractility, was paralleled by accumulation of autophagy-related markers and loss of acute responsiveness to both colchicine and chloroquine. These changes were correlated with elevated levels of damaged proteins, chaperones and pro-apoptotic markers compared to control animals. Sustained autophagy inhibition using chloroquine in rats (50 mg.kg -1 .day -1 ) or muscle-specific deletion of Atg7 in mice was sufficient to impair muscle contractility in control but not in neurogenic myopathy, suggesting that dysfunctional autophagy is critical in skeletal muscle pathophysiology. Finally, 4 weeks of aerobic exercise training (moderate treadmill running, 5x/week, 1 h/day) prior to neurogenic myopathy improved skeletal muscle autophagic flux and proteostasis. These changes were followed by spared muscle mass and better contractility properties. Taken together, our findings suggest the potential value of exercise in maintaining skeletal muscle proteostasis and slowing down the progression of neurogenic myopathy.

Aims: The current study tested the hypotheses that 1) an acute bout of aerobic exercise impairs isolated skeletal muscle contractile properties and 2) N-acetylcysteine (a thiol antioxidant; NAC) administration can restore the impaired muscle contractility after exercise., Main Methods: At rest or immediately after an acute bout of aerobic exercise, extensor digitorum longus (EDL) and soleus muscles from male Wistar rats were harvested for ex vivo skeletal muscle contraction experiments. Muscles from exercised animals were incubated in Krebs Ringer's buffer in absence or presence of 20mM of NAC. Force capacity and fatigue properties were evaluated., Key Findings: Exercised EDL and soleus displayed lower force production across various stimulation frequencies (p<0.001), indicating that skeletal muscle force production was impaired after an acute bout of exercise. However, NAC treatment restored the loss of force production in both EDL and soleus after fatiguing exercise (p<0.05). Additionally, NAC treatment increased relative force production at different time points during a fatigue-induced protocol, suggesting that NAC treatment mitigates fatigue induced by successive contractions., Significance: NAC treatment improves force capacity and fatigue properties in ex vivo skeletal muscle from rats submitted to an acute bout of aerobic exercise., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We have recently demonstrated that NADPH oxidase hyperactivity, NF-κB activation, and increased p38 phosphorylation lead to atrophy of glycolytic muscle in heart failure (HF). Aerobic exercise training (AET) is an efficient strategy to counteract skeletal muscle atrophy in this syndrome. Therefore, we tested whether AET would regulate muscle redox balance and protein degradation by decreasing NADPH oxidase hyperactivity and reestablishing NF-κB signaling, p38 phosphorylation, and proteasome activity in plantaris muscle of myocardial infarcted-induced HF (MI) rats. Thirty-two male Wistar rats underwent MI or fictitious surgery (SHAM) and were randomly assigned into untrained (UNT) and trained (T; 8 wk of AET on treadmill) groups. AET prevented HF signals and skeletal muscle atrophy in MI-T, which showed an improved exercise tolerance, attenuated cardiac dysfunction and increased plantaris fiber cross-sectional area. To verify the role of inflammation and redox imbalance in triggering protein degradation, circulating TNF-α levels, NADPH oxidase profile, NF-κB signaling, p38 protein levels, and proteasome activity were assessed. MI-T showed a reduced TNF-α levels, NADPH oxidase activity, and Nox2 mRNA expression toward SHAM-UNT levels. The rescue of NADPH oxidase activity induced by AET in MI rats was paralleled by reducing nuclear binding activity of the NF-κB, p38 phosphorylation, atrogin-1, mRNA levels, and 26S chymotrypsin-like proteasome activity. Taken together our data provide evidence for AET improving plantaris redox homeostasis in HF associated with a decreased NADPH oxidase, redox-sensitive proteins activation, and proteasome hyperactivity further preventing atrophy. These data reinforce the role of AET as an efficient therapy for muscle wasting in HF. NEW & NOTEWORTHY This study demonstrates, for the first time, the contribution of aerobic exercise training (AET) in decreasing muscle NADPH oxidase activity associated with reduced reactive oxygen species production and systemic inflammation, which diminish NF-κB overactivation, p38 phosphorylation, and ubiquitin proteasome system hyperactivity. These molecular changes counteract plantaris atrophy in trained myocardial infarction-induced heart failure rats. Our data provide new evidence into how AET may regulate protein degradation and thus prevent skeletal muscle atrophy., (Copyright © 2017 the American Physiological Society.)

Cardiac endoplasmic reticulum (ER) stress through accumulation of misfolded proteins plays a pivotal role in cardiovascular diseases. In an attempt to reestablish ER homoeostasis, the unfolded protein response (UPR) is activated. However, if ER stress persists, sustained UPR activation leads to apoptosis. There is no available therapy for ER stress relief. Considering that aerobic exercise training (AET) attenuates oxidative stress, mitochondrial dysfunction and calcium imbalance, it may be a potential strategy to reestablish cardiac ER homoeostasis. We test the hypothesis that AET would attenuate impaired cardiac ER stress after myocardial infarction (MI). Wistar rats underwent to either MI or sham surgeries. Four weeks later, rats underwent to 8 weeks of moderate-intensity AET. Myocardial infarction rats displayed cardiac dysfunction and lung oedema, suggesting heart failure. Cardiac dysfunction in MI rats was paralleled by increased protein levels of UPR markers (GRP78, DERLIN-1 and CHOP), accumulation of misfolded and polyubiquitinated proteins, and reduced chymotrypsin-like proteasome activity. These results suggest an impaired cardiac protein quality control. Aerobic exercise training improved exercise capacity and cardiac function of MI animals. Interestingly, AET blunted MI-induced ER stress by reducing protein levels of UPR markers, and accumulation of both misfolded and polyubiquinated proteins, which was associated with restored proteasome activity. Taken together, our study provide evidence for AET attenuation of ER stress through the reestablishment of cardiac protein quality control, which contributes to better cardiac function in post-MI heart failure rats. These results reinforce the importance of AET as primary non-pharmacological therapy to cardiovascular disease., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Skeletal myopathy has been identified as a major comorbidity of heart failure (HF) affecting up to 20% of ambulatory patients leading to shortness of breath, early fatigue, and exercise intolerance. Neurohumoral blockade, through the inhibition of renin angiotensin aldosterone system (RAS) and β-adrenergic receptor blockade (β-blockers), is a mandatory pharmacological therapy of HF since it reduces symptoms, mortality, and sudden death. However, the effect of these drugs on skeletal myopathy needs to be clarified, since exercise intolerance remains in HF patients optimized with β-blockers and inhibitors of RAS. Aerobic exercise training (AET) is efficient in counteracting skeletal myopathy and in improving functional capacity and quality of life. Indeed, AET has beneficial effects on failing heart itself despite being of less magnitude compared with neurohumoral blockade. In this way, AET should be implemented in the care standards, together with pharmacological therapies. Since both neurohumoral inhibition and AET have a direct and/or indirect impact on skeletal muscle, this review aims to provide an overview of the isolated effects of these therapeutic approaches in counteracting skeletal myopathy in HF. The similarities and dissimilarities of neurohumoral inhibition and AET therapies are also discussed to identify potential advantageous effects of these combined therapies for treating HF.

Background: Skeletal muscle wasting is associated with poor prognosis and increased mortality in heart failure (HF) patients. Glycolytic muscles are more susceptible to catabolic wasting than oxidative ones. This is particularly important in HF since glycolytic muscle wasting is associated with increased levels of reactive oxygen species (ROS). However, the main ROS sources involved in muscle redox imbalance in HF have not been characterized. Therefore, we hypothesized that NADPH oxidases would be hyperactivated in the plantaris muscle of infarcted rats, contributing to oxidative stress and hyperactivation of the ubiquitin-proteasome system (UPS), ultimately leading to atrophy., Methods: Rats were submitted to myocardial infarction (MI) or Sham surgery. Four weeks after surgery, MI and Sham groups underwent eight weeks of treatment with apocynin, a NADPH oxidase inhibitor, or placebo. NADPH oxidase activity, oxidative stress markers, NF-κB activity, p38 MAPK phosphorylation, mRNA and sarcolemmal protein levels of NADPH oxidase components, UPS activation and fiber cross-sectional area were assessed in the plantaris muscle., Results: The plantaris of MI rats displayed atrophy associated with increased Nox2 mRNA and sarcolemmal protein levels, NADPH oxidase activity, ROS production, lipid hydroperoxides levels, NF-κB activity, p38 MAPK phosphorylation and UPS activation. NADPH oxidase inhibition by apocynin prevented MI-induced skeletal muscle atrophy by reducing ROS production, NF-κB hyperactivation, p38 MAPK phosphorylation and proteasomal hyperactivity., Conclusion: Our data provide evidence for NADPH oxidase hyperactivation as an important source of ROS production leading to plantaris atrophy in heart failure rats, suggesting that this enzyme complex plays key role in skeletal muscle wasting in HF., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Skeletal myopathy is a hallmark of heart failure (HF) and has been associated with a poor prognosis. HF and other chronic degenerative diseases share a common feature of a stressed system: sympathetic hyperactivity. Although beneficial acutely, chronic sympathetic hyperactivity is one of the main triggers of skeletal myopathy in HF. Considering that β2 -adrenoceptors mediate the activity of sympathetic nervous system in skeletal muscle, we presently evaluated the contribution of β2 -adrenoceptors for the morphofunctional alterations in skeletal muscle and also for exercise intolerance induced by HF. Male WT and β2 -adrenoceptor knockout mice on a FVB genetic background (β2 KO) were submitted to myocardial infarction (MI) or SHAM surgery. Ninety days after MI both WT and β2 KO mice presented to cardiac dysfunction and remodelling accompanied by significantly increased norepinephrine and epinephrine plasma levels, exercise intolerance, changes towards more glycolytic fibres and vascular rarefaction in plantaris muscle. However, β2 KO MI mice displayed more pronounced exercise intolerance and skeletal myopathy when compared to WT MI mice. Skeletal muscle atrophy of infarcted β2 KO mice was paralleled by reduced levels of phosphorylated Akt at Ser 473 while increased levels of proteins related with the ubiquitin--proteasome system, and increased 26S proteasome activity. Taken together, our results suggest that lack of β2 -adrenoceptors worsen and/or anticipate the skeletal myopathy observed in HF., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Aims: Increased cardiac sympathetic neuron (SN) activity has been associated with pathologies such as heart failure and hypertrophy, suggesting that cardiac innervation regulates cardiomyocyte trophism. Whether continuous input from the SNs is required for the maintenance of the cardiomyocyte size has not been determined thus far., Methods and Results: To address the role of cardiac innervation in cardiomyocyte size regulation, we monitored the effect of pharmacological sympathetic denervation in mice on cardiac structure, function, and signalling from 24 h to 30 days in the absence of other pathological stimuli. SN ablation caused an immediate reduction in the cardiomyocyte size with minimal consequences on the resting contractile function. Atrophic remodelling was mediated by the ubiquitin-proteasome system through FOXO-dependent early induction of the muscle-specific E3 ubiquitin ligases Atrogin-1/MAFbx and MuRF1, which was followed by activation of the autophagy-lysosome system. MuRF1 was found to be determinant in denervation atrophy as remodelling did not develop in denervated MuRF1 knock-out (KO) hearts. These effects were caused by decreased basal stimulation of cardiomyocyte β2-adrenoceptor (AR), as atrophy was prevented by treatment of denervated mice with the β2-AR agonist clenbuterol. Consistent with these data, we also observed that β2-AR KO mice showed cardiac atrophy at rest., Conclusion: Cardiac SNs are strong regulators of the cardiomyocyte size via β2-AR-dependent repression of proteolysis, demonstrating that the neuro-cardiac axis operates constitutively for the determination of the physiological cardiomyocyte size. These results are of great clinical relevance given the role of β-AR in cardiovascular diseases and their modulation in therapy.

β(2)-adrenergic receptor (β(2)-AR) agonists have been used as ergogenics by athletes involved in training for strength and power in order to increase the muscle mass. Even though anabolic effects of β(2)-AR activation are highly recognized, less is known about the impact of β(2)-AR in endurance capacity. We presently used mice lacking β(2)-AR [β(2)-knockout (β(2) KO)] to investigate the role of β(2)-AR on exercise capacity and skeletal muscle metabolism and phenotype. β(2) KO mice and their wild-type controls (WT) were studied. Exercise tolerance, skeletal muscle fiber typing, capillary-to-fiber ratio, citrate synthase activity and glycogen content were evaluated. When compared with WT, β(2) KO mice displayed increased exercise capacity (61%) associated with higher percentage of oxidative fibers (21% and 129% of increase in soleus and plantaris muscles, respectively) and capillarity (31% and 20% of increase in soleus and plantaris muscles, respectively). In addition, β(2) KO mice presented increased skeletal muscle citrate synthase activity (10%) and succinate dehydrogenase staining. Likewise, glycogen content (53%) and periodic acid-Schiff staining (glycogen staining) were also increased in β(2) KO skeletal muscle. Altogether, these data provide evidence that disruption of β(2)-AR improves oxidative metabolism in skeletal muscle of β(2) KO mice and this is associated with increased exercise capacity., (© 2012 John Wiley & Sons A/S.)

The present investigation was undertaken to test whether exercise training (ET) associated with AMPK/PPAR agonists (EM) would improve skeletal muscle function in mdx mice. These drugs have the potential to improve oxidative metabolism. This is of particular interest because oxidative muscle fibers are less affected in the course of the disease than glycolitic counterparts. Therefore, a cohort of 34 male congenic C57Bl/10J mdx mice included in this study was randomly assigned into four groups: vehicle solution (V), EM [AICAR (AMPK agonist, 50 mg/Kg-1.day-1, ip) and GW 1516 (PPARδ agonist, 2.5 mg/Kg-1.day-1, gavage)], ET (voluntary running on activity wheel) and EM+ET. Functional performance (grip meter and rotarod), aerobic capacity (running test), muscle histopathology, serum creatine kinase (CK), levels of ubiquitined proteins, oxidative metabolism protein expression (AMPK, PPAR, myoglobin and SCD) and intracellular calcium handling (DHPR, SERCA and NCX) protein expression were analyzed. Treatments started when the animals were two months old and were maintained for one month. A significant functional improvement (p<0.05) was observed in animals submitted to the combination of ET and EM. CK levels were decreased and the expression of proteins related to oxidative metabolism was increased in this group. There were no differences among the groups in the intracellular calcium handling protein expression. To our knowledge, this is the first study that tested the association of ET with EM in an experimental model of muscular dystrophy. Our results suggest that the association of ET and EM should be further tested as a potential therapeutic approach in muscular dystrophies.

Skeletal muscle protein turnover is modulated by intracellular signaling pathways involved in protein synthesis, degradation, and inflammation. The proinflammatory status of muscle cells, observed in pathological conditions such as cancer, aging, and sepsis, can directly modulate protein translation initiation and muscle proteolysis, contributing to negative protein turnover. In this context, branched-chain amino acids (BCAAs), especially leucine, have been described as a strong nutritional stimulus able to enhance protein translation initiation and attenuate proteolysis. Furthermore, under inflammatory conditions, BCAA can be transaminated to glutamate in order to increase glutamine synthesis, which is a substrate highly consumed by inflammatory cells such as macrophages. The present paper describes the role of inflammation on muscle remodeling and the possible metabolic and cellular effects of BCAA supplementation in the modulation of inflammatory status of skeletal muscle and the consequences on protein synthesis and degradation.