Beneficial Effects of Oral Carbon Monoxide on Doxorubicin-Induced Cardiotoxicity.

BACKGROUND: Doxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI-002) that can be easily self-administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract. METHODS AND RESULTS: HBI-002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI-002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI-002 had a 6.3-fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase-1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI-002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI-002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function. CONCLUSIONS: These findings strongly support using HBI-002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage.

Aerobic exercise training mitigates tumor growth and cancer-induced splenomegaly through modulation of non-platelet platelet factor 4 expression.

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.

Heme: The Lord of the Iron Ring.

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.

Carbon monoxide and a change of heart.

The relationship between carbon monoxide and the heart has been extensively studied in both clinical and preclinical settings. The Food and Drug Administration (FDA) is keenly focused on the ill effects of carbon monoxide on the heart when presented with proposals for clinical trials to evaluate efficacy of this gasotransmitter in a various disease settings. This review provides an overview of the rationale that examines the actions of the FDA when considering clinical testing of CO, and contrast that with the continued accumulation of data that clearly show not only that CO can be used safely, but is potently cardioprotective in clinically relevant small and large animal models. Data emerging from Phase I and Phase II clinical trials argues against CO being dangerous to the heart and thus it needs to be redefined and evaluated as any other substance being proposed for use in humans. More than twenty years ago, the belief that CO could be used as a salutary molecule was ridiculed by experts in physiology and medicine. Like all agents designed for use in humans, careful pharmacology and safety are paramount, but continuing to hinder progress based on long-standing dogma in the absence of data is improper. Now, CO is being tested in multiple clinical trials using innovative delivery methods and has proven to be safe. The hope, based on compelling preclinical data, is that it will continue to be evaluated and ultimately approved as an effective therapeutic.

Physiological Responses to Maximal and Submaximal Walking in Patients with Symptomatic Peripheral Artery Disease. / Respostas Fisiológicas à Caminhada Máxima e Submáxima em Pacientes com Doença Arterial Periférica Sintomática.

BACKGROUND: Although maximal and submaximal walking are recommended for patients with peripheral artery disease (PAD), performing these exercises may induce different physiological responses. OBJECTIVES: To compare the acute effects of maximal and submaximal walking on post-exercise cardiovascular function, regulation, and associated pathophysiological processes in patients with symptomatic PAD. METHODS: Thirty male patients underwent 2 sessions: maximal walking (Gardner's protocol) and submaximal walking (15 bouts of 2 minutes of walking separated by 2 minutes of upright rest). In each session, blood pressure (BP), heart rate (HR), cardiac autonomic modulation (HR variability), forearm and calf blood flows (BF), vasodilatory capacity (reactive hyperemia), nitric oxide (NO), oxidative stress (lipid peroxidation), and inflammation (four markers) were measured pre- and post-walking. ANOVAs were employed, and p < 0.05 was considered significant. RESULTS: Systolic and mean BP decreased after the submaximal session, but they increased after the maximal session (interactions, p < 0.001 for both). Diastolic BP did not change after the submaximal session (p > 0.05), and it increased after maximal walking (interaction, p < 0.001). HR, sympathovagal balance, and BF increased similarly after both sessions (moment, p < 0.001, p = 0.04, and p < 0.001, respectively), while vasodilatory capacity, NO, and oxidative stress remained unchanged (p > 0.05). Vascular and intercellular adhesion molecules increased similarly after both maximal and submaximal walking sessions (moment, p = 0.001). CONCLUSIONS: In patients with symptomatic PAD, submaximal, but not maximal walking reduced post-exercise BP, while maximal walking maintained elevated cardiac overload during the recovery period. On the other hand, maximal and submaximal walking sessions similarly increased post-exercise HR, cardiac sympathovagal balance, and inflammation, while they did not change post-exercise NO bioavailability and oxidative stress.

FUNDAMENTO: Embora a caminhada máxima e submáxima sejam recomendadas para pacientes com doença arterial periférica (DAP), a realização desses exercícios pode induzir diferentes respostas fisiológicas. OBJETIVOS: Comparar os efeitos agudos de caminhada máxima e submáxima na função cardiovascular, a regulação e os processos fisiopatológicos associados pós-exercício em pacientes com DAP sintomática. MÉTODOS: Trinta pacientes do sexo masculino foram submetidos a 2 sessões: caminhada máxima (protocolo de Gardner) e caminhada submáxima (15 períodos de 2 minutos de caminhada separados por 2 minutos de repouso ereto). Em cada sessão, foram medidos a pressão arterial (PA), a frequência cardíaca (FC), a modulação autonômica cardíaca (variabilidade da FC), os fluxos sanguíneos (FS) do antebraço e da panturrilha, a capacidade vasodilatadora (hiperemia reativa), o óxido nítrico (ON), o estresse oxidativo (a peroxidação lipídica) e a inflamação (quatro marcadores), pré e pós-caminhada. ANOVAs foram empregadas e p < 0,05 foi considerado significativo. RESULTADOS: A PA sistólica e a PA média diminuíram após a sessão submáxima, mas aumentaram após a sessão máxima (interações, p < 0,001 para ambas). A PA diastólica não foi alterada após a sessão submáxima (p > 0,05), mas aumentou após a caminhada máxima (interação, p < 0,001). A FC, o equilíbrio simpatovagal e os FS aumentaram de forma semelhante após as duas sessões (momento, p < 0,001, p = 0,04 e p < 0,001, respectivamente), enquanto a capacidade vasodilatadora, o ON e o estresse oxidativo permaneceram inalterados (p > 0,05). As moléculas de adesão vascular e intercelular aumentaram de forma semelhante após as sessões de caminhada máxima e submáxima (momento, p = 0,001). CONCLUSÕES: Nos pacientes com a DAP sintomática, a caminhada submáxima, mas não a máxima, reduziu a PA pós-exercício, enquanto a caminhada máxima manteve a sobrecarga cardíaca elevada durante o período de recuperação. Por outro lado, as sessões de caminhada máxima e submáxima aumentaram a FC, o equilíbrio simpatovagal cardíaco e a inflamação pós-exercício de forma semelhante, enquanto não alteraram a biodisponibilidade de ON e o estresse oxidativo pós-exercício.

Trauma-induced heme release increases susceptibility to bacterial infection.

Infection is a common complication of major trauma that causes significantly increased morbidity and mortality. The mechanisms, however, linking tissue injury to increased susceptibility to infection remain poorly understood. To study this relationship, we present a potentially novel murine model in which a major liver crush injury is followed by bacterial inoculation into the lung. We find that such tissue trauma both impaired bacterial clearance and was associated with significant elevations in plasma heme levels. While neutrophil (PMN) recruitment to the lung in response to Staphylococcus aureus was unchanged after trauma, PMN cleared bacteria poorly. Moreover, PMN show > 50% less expression of TLR2, which is responsible, in part, for bacterial recognition. Administration of heme effectively substituted for trauma. Finally, day 1 trauma patients (n = 9) showed similar elevations in free heme compared with that seen after murine liver injury, and circulating PMN showed similar TLR2 reduction compared with volunteers (n = 6). These findings correlate to high infection rates.

Respostas fisiológicas à caminhada máxima e submáxima em pacientes com doença arterial periférica sintomática / Physiological responses to maximal and submaximal walking in patients with symptomatic peripheral artery disease

Resumo Fundamento: Embora a caminhada máxima e submáxima sejam recomendadas para pacientes com doença arterial periférica (DAP), a realização desses exercícios pode induzir diferentes respostas fisiológicas. Objetivos: Comparar os efeitos agudos de caminhada máxima e submáxima na função cardiovascular, a regulação e os processos fisiopatológicos associados pós-exercício em pacientes com DAP sintomática. Métodos: Trinta pacientes do sexo masculino foram submetidos a 2 sessões: caminhada máxima (protocolo de Gardner) e caminhada submáxima (15 períodos de 2 minutos de caminhada separados por 2 minutos de repouso ereto). Em cada sessão, foram medidos a pressão arterial (PA), a frequência cardíaca (FC), a modulação autonômica cardíaca (variabilidade da FC), os fluxos sanguíneos (FS) do antebraço e da panturrilha, a capacidade vasodilatadora (hiperemia reativa), o óxido nítrico (ON), o estresse oxidativo (a peroxidação lipídica) e a inflamação (quatro marcadores), pré e pós-caminhada. ANOVAs foram empregadas e p < 0,05 foi considerado significativo. Resultados: A PA sistólica e a PA média diminuíram após a sessão submáxima, mas aumentaram após a sessão máxima (interações, p < 0,001 para ambas). A PA diastólica não foi alterada após a sessão submáxima (p > 0,05), mas aumentou após a caminhada máxima (interação, p < 0,001). A FC, o equilíbrio simpatovagal e os FS aumentaram de forma semelhante após as duas sessões (momento, p < 0,001, p = 0,04 e p < 0,001, respectivamente), enquanto a capacidade vasodilatadora, o ON e o estresse oxidativo permaneceram inalterados (p > 0,05). As moléculas de adesão vascular e intercelular aumentaram de forma semelhante após as sessões de caminhada máxima e submáxima (momento, p = 0,001). Conclusões: Nos pacientes com a DAP sintomática, a caminhada submáxima, mas não a máxima, reduziu a PA pós-exercício, enquanto a caminhada máxima manteve a sobrecarga cardíaca elevada durante o período de recuperação. Por outro lado, as sessões de caminhada máxima e submáxima aumentaram a FC, o equilíbrio simpatovagal cardíaco e a inflamação pós-exercício de forma semelhante, enquanto não alteraram a biodisponibilidade de ON e o estresse oxidativo pós-exercício.

Abstract Background: Although maximal and submaximal walking are recommended for patients with peripheral artery disease (PAD), performing these exercises may induce different physiological responses. Objectives: To compare the acute effects of maximal and submaximal walking on post-exercise cardiovascular function, regulation, and associated pathophysiological processes in patients with symptomatic PAD. Methods: Thirty male patients underwent 2 sessions: maximal walking (Gardner's protocol) and submaximal walking (15 bouts of 2 minutes of walking separated by 2 minutes of upright rest). In each session, blood pressure (BP), heart rate (HR), cardiac autonomic modulation (HR variability), forearm and calf blood flows (BF), vasodilatory capacity (reactive hyperemia), nitric oxide (NO), oxidative stress (lipid peroxidation), and inflammation (four markers) were measured pre- and post-walking. ANOVAs were employed, and p < 0.05 was considered significant. Results: Systolic and mean BP decreased after the submaximal session, but they increased after the maximal session (interactions, p < 0.001 for both). Diastolic BP did not change after the submaximal session (p > 0.05), and it increased after maximal walking (interaction, p < 0.001). HR, sympathovagal balance, and BF increased similarly after both sessions (moment, p < 0.001, p = 0.04, and p < 0.001, respectively), while vasodilatory capacity, NO, and oxidative stress remained unchanged (p > 0.05). Vascular and intercellular adhesion molecules increased similarly after both maximal and submaximal walking sessions (moment, p = 0.001). Conclusions: In patients with symptomatic PAD, submaximal, but not maximal walking reduced post-exercise BP, while maximal walking maintained elevated cardiac overload during the recovery period. On the other hand, maximal and submaximal walking sessions similarly increased post-exercise HR, cardiac sympathovagal balance, and inflammation, while they did not change post-exercise NO bioavailability and oxidative stress.

Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity.

Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1fl/fl) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1fl/fl mice show remarkable muscle atrophy compared to Hmox1fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.

Walking Training Improves Systemic and Local Pathophysiological Processes in Intermittent Claudication.

OBJECTIVE: This study examined the impact of submaximal walking training (WT) on local and systemic nitric oxide (NO) bioavailability, inflammation, and oxidative stress in patients with intermittent claudication (IC). METHODS: The study employed a randomised, controlled, parallel group design and was performed in a single centre. Thirty-two men with IC were randomly allocated to two groups: WT (n = 16, two sessions/week, 15 cycles of two minutes walking at an intensity corresponding to the heart rate obtained at the pain threshold interspersed by two minutes of upright rest) and control (CO, n = 16, two sessions/week, 30 minutes of stretching). NO bioavailability (blood NO and muscle nitric oxide synthase [eNOS]), redox homeostasis (catalase [CAT], superoxide dismutase [SOD], lipid peroxidation [LPO] measured in blood and muscle), and inflammation (interleukin-6 [IL-6], C-reactive protein [CRP], tumour necrosis factor α [TNF-α], intercellular adhesion molecules [ICAM], vascular adhesion molecules [VCAM] measured in blood and muscle) were assessed at baseline and after 12 weeks. RESULTS: WT statistically significantly increased blood NO, muscle eNOS, blood SOD and CAT, and muscle SOD and abolished the increase in circulating and muscle LPO observed in the CO group. WT decreased blood CRP, ICAM, and VCAM and muscle IL-6 and CRP and eliminated the increase in blood TNF-α and muscle TNF-α, ICAM and VCAM observed in the CO group. CONCLUSION: WT at an intensity of pain threshold improved NO bioavailability and decreased systemic and local oxidative stress and inflammation in patients with IC. The proposed WT protocol provides physiological adaptations that may contribute to cardiovascular health in these patients.

Local and Systemic Inflammation and Oxidative Stress After a Single Bout of Maximal Walking in Patients With Symptomatic Peripheral Artery Disease.

OBJECTIVE: The aim of this study was to assess the effects of a single bout of maximal walking on blood and muscle nitric oxide (NO) bioavailability, oxidative stress, and inflammation in symptomatic peripheral artery disease (PAD) patients. METHODS: A total of 35 men with symptomatic PAD performed a graded maximal exercise test on a treadmill (3.2 km/h, 2% increase in grade every 2 minutes). Plasma samples and gastrocnemius muscle biopsies were collected preexercise and postexercise for assessment of NO bioavailability (plasma NO and muscle, endothelial NO synthase), oxidative stress and antioxidant function (lipid peroxidation [LPO], catalase [CAT], and superoxide dismutase), and inflammation (interleukin-6, C-reactive protein, tumor necrosis factor-α, intercellular adhesion molecules, and vascular adhesion molecules). The effects of the walking exercise were assessed using paired t tests or Wilcoxon tests. RESULTS: After maximal walking, plasma NO and LPO were unchanged (P > .05), plasma CAT decreased, and all blood inflammatory markers increased (all P ≤ .05). In the disease-affected skeletal muscle, endothelial NO synthase, CAT, LPO, and all inflammatory markers increased, whereas superoxide dismutase decreased (all P ≤ .05). CONCLUSION: In patients with symptomatic PAD, maximal exercise induces local and systemic impairments, which may play a key role in atherogenesis. Exercise strategies that avoid maximal effort may be important to reduce local and systemic damage and enhance clinical benefits.

Adaptive Potential of the Heme Oxygenase/Carbon Monoxide Pathway During Hypoxia.

Heme oxygenase (HO) enzymes catalyze heme into biliverdin, releasing carbon monoxide (CO) and iron into circulation. These byproducts of heme degradation can have potent cytoprotective effects in the face of stressors such as hypoxia and ischemia-reperfusion events. The potential for exogenous use of CO as a therapeutic agent has received increasing attention throughout the past few decades. Further, HO and CO are noted as putatively adaptive in diving mammals and certain high-altitude human populations that are frequently exposed to hypoxia and/or ischemia-reperfusion events, suggesting that HO and endogenous CO afford an evolutionary advantage for hypoxia tolerance and are critical in cell survival and injury avoidance. Our goal is to describe the importance of examining HO and CO in several systems, the physiological links, and the genetic factors that underlie variation in the HO/CO pathway. Finally, we emphasize the ways in which evolutionary perspectives may enhance our understanding of the HO/CO pathway in the context of diverse clinical settings.

Intense resistance training induces pronounced metabolic stress and impairs hypertrophic response in hind-limb muscles of rats.

Skeletal muscle hypertrophy is an exercise-induced adaptation, particularly in resistance training (RT) programs that use large volumes and low loads. However, evidence regarding the role of rest intervals on metabolic stress and muscular adaptations is inconclusive. Thus, we aimed to investigate the effects of a strenuous RT model (jump-training) on skeletal muscle adaptations and metabolic stress, considering the scarce information about RT models for rats. We hypothesized that jump-training induces metabolic stress and influences negatively the growth of soleus (SOL) and extensor digitorum longus (EDL) muscles of rats. Male Wistar rats (aged 60 days) were randomly assigned to non-trained or trained groups (n = 8/group). Trained rats performed jump-training during 5 days a week for 1, 3, or 5 weeks with 30 s of inter-set rest intervals. Forty-eight hours after the experimental period, rats were euthanized and blood samples immediately drawn to measure creatine kinase activity, lactate and corticosterone concentrations. Muscle weight-to-body weight ratio (MW/BW), cross-sectional area (CSA) and myosin heavy chain (MHC) isoform expression were determined. Higher lactate levels occurred after 20 min of training in weeks 1 and 3. Corticosterone levels were higher after 5 weeks of training. Jump-training had negative effects on hypertrophy of types-I and II muscle fibers after 5 weeks of training, as evidenced by decreased CSA and reduced muscle weight. Our results demonstrated that pronounced metabolic stress and impairment of muscle growth might take place when variables of exercise training are not appropriately manipulated. Lay summary Resistance training (RT) has been used to increase muscle mass. In this regard, training variables (intensity, volume, and frequency) must be strictly controlled in order to evoke substantial muscular fitness. This study shows that rats submitted to 5 weeks of intensive resistance jump-training - high intensity, large volume, and short rest intervals - present high levels of blood corticosterone associated with negative effects on hypertrophy of types-I and II muscle fibers.

Differential regulation of cysteine oxidative post-translational modifications in high and low aerobic capacity.

Given the association between high aerobic capacity and the prevention of metabolic diseases, elucidating the mechanisms by which high aerobic capacity regulates whole-body metabolic homeostasis is a major research challenge. Oxidative post-translational modifications (Ox-PTMs) of proteins can regulate cellular homeostasis in skeletal and cardiac muscles, but the relationship between Ox-PTMs and intrinsic components of oxidative energy metabolism is still unclear. Here, we evaluated the Ox-PTM profile in cardiac and skeletal muscles of rats bred for low (LCR) and high (HCR) intrinsic aerobic capacity. Redox proteomics screening revealed different cysteine (Cys) Ox-PTM profile between HCR and LCR rats. HCR showed a higher number of oxidized Cys residues in skeletal muscle compared to LCR, while the opposite was observed in the heart. Most proteins with differentially oxidized Cys residues in the skeletal muscle are important regulators of oxidative metabolism. The most oxidized protein in the skeletal muscle of HCR rats was malate dehydrogenase (MDH1). HCR showed higher MDH1 activity compared to LCR in skeletal, but not cardiac muscle. These novel findings indicate a clear association between Cys Ox-PTMs and aerobic capacity, leading to novel insights into the role of Ox-PTMs as an essential signal to maintain metabolic homeostasis.

Integration of miRNA and mRNA expression profiles reveals microRNA-regulated networks during muscle wasting in cardiac cachexia.

Cardiac cachexia (CC) is a common complication of heart failure (HF) associated with muscle wasting and poor patient prognosis. Although different mechanisms have been proposed to explain muscle wasting during CC, its pathogenesis is still not understood. Here, we described an integrative analysis between miRNA and mRNA expression profiles of muscle wasting during CC. Global gene expression profiling identified 1,281 genes and 19 miRNAs differentially expressed in muscle wasting during CC. Several of these deregulated genes are known or putative targets of the altered miRNAs, including miR-29a-3p, miR-29b-3p, miR-210-5p, miR-214, and miR-489. Gene ontology analysis on integrative mRNA/miRNA expression profiling data revealed miRNA interactions affecting genes that regulate extra-cellular matrix (ECM) organization, proteasome protein degradation, citric acid cycle and respiratory electron transport. We further identified 11 miRNAs, including miR-29a-3p and miR-29b-3p, which target 21 transcripts encoding the collagen proteins related to ECM organization. Integrative miRNA and mRNA global expression data allowed us to identify miRNA target genes involved in skeletal muscle wasting in CC. Our functional experiments in C2C12 cells confirmed that miR-29b down-regulates collagen genes and contributes to muscle cell atrophy. Collectively, our results suggest that key ECM-associated miRNAs and their target genes may contribute to CC in HF.

Aerobic Exercise and Pharmacological Therapies for Skeletal Myopathy in Heart Failure: Similarities and Differences.

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 ß-adrenergic receptor blockade (ß-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 ß-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.

Aerobic Exercise Recovers Disuse-induced Atrophy Through the Stimulus of the LRP130/PGC-1α Complex in Aged Rats.

Physical training has been shown to be important to the control of muscle mass during aging, through the activation of several pathways including, IGF1-AKT and PGC-1α. Also, it was demonstrated that LRP130, a component of the PGC-1α complex, is important for the PGC-1α-dependent transcription of several mitochondrial genes in vivo. To explore the role of physical training during aging, we investigated the effects on muscle recovery after short-term immobilization followed by 3 or 7 days with aerobic or resistance training. Using morphological (myofibrillar adenosine triphosphatase activity, to assess the total muscle fiber cross-sectional area (CSA) and the frequency of specific fiber types), biochemical (myosin heavy chain), and molecular analyses (quantitative real-time PCR, functional pathways analyses, and Western blot), our results indicated that after an atrophic stimulus, only animals subjected to aerobic training showed entire recovery of cross-sectional area; aerobic training reduced the ubiquitin-proteasome system components involved in muscle atrophy after 3 days of recovery, and the upregulation in PGC-1α expression enhanced the process of muscle recovery by inhibiting the FoxO pathway, with the possible involvement of LRP130. These results suggest that aerobic training enhanced the muscle regeneration process after disuse-induced atrophy in aged rats possibly through of the LRP130/PGC-1α complex by inhibiting the ubiquitin-proteasome system.

Regulation of cardiac microRNAs induced by aerobic exercise training during heart failure.

Exercise training (ET) has beneficial effects on the myocardium in heart failure (HF) patients and in animal models of induced cardiac hypertrophy and failure. We hypothesized that if microRNAs (miRNAs) respond to changes following cardiac stress, then myocardial profiling of these miRNAs may reveal cardio-protective mechanisms of aerobic ET in HF. We used ascending aortic stenosis (AS) inducing HF in Wistar rats. Controls were sham-operated animals. At 18 wk after surgery, rats with cardiac dysfunction were randomized to 10 wk of aerobic ET (HF-ET) or to a heart failure sedentary group (HF-S). ET attenuated cardiac remodeling as well as clinical and pathological signs of HF with maintenance of systolic and diastolic function when compared with that of the HF-S. Global miRNA expression profiling of the cardiac tissue revealed 53 miRNAs exclusively dysregulated in animals in the HF-ET, but only 11 miRNAs were exclusively dysregulated in the HF-S. Out of 23 miRNAs that were differentially regulated in both groups, 17 miRNAs exhibited particularly high increases in expression, including miR-598, miR-429, miR-224, miR-425, and miR-221. From the initial set of deregulated miRNAs, 14 miRNAs with validated targets expressed in cardiac tissue that respond robustly to ET in HF were used to construct miRNA-mRNA regulatory networks that revealed a set of 203 miRNA-target genes involved in programmed cell death, TGF-ß signaling, cellular metabolic processes, cytokine signaling, and cell morphogenesis. Our findings reveal that ET attenuates cardiac abnormalities during HF by regulating cardiac miRNAs with a potential role in cardio-protective mechanisms through multiple effects on gene expression.

Aerobic exercise training prevents heart failure-induced skeletal muscle atrophy by anti-catabolic, but not anabolic actions.

BACKGROUND: Heart failure (HF) is associated with cachexia and consequent exercise intolerance. Given the beneficial effects of aerobic exercise training (ET) in HF, the aim of this study was to determine if the ET performed during the transition from cardiac dysfunction to HF would alter the expression of anabolic and catabolic factors, thus preventing skeletal muscle wasting. METHODS AND RESULTS: We employed ascending aortic stenosis (AS) inducing HF in Wistar male rats. Controls were sham-operated animals. At 18 weeks after surgery, rats with cardiac dysfunction were randomized to 10 weeks of aerobic ET (AS-ET) or to an untrained group (AS-UN). At 28 weeks, the AS-UN group presented HF signs in conjunction with high TNF-α serum levels; soleus and plantaris muscle atrophy; and an increase in the expression of TNF-α, NFκB (p65), MAFbx, MuRF1, FoxO1, and myostatin catabolic factors. However, in the AS-ET group, the deterioration of cardiac function was prevented, as well as muscle wasting, and the atrophy promoters were decreased. Interestingly, changes in anabolic factor expression (IGF-I, AKT, and mTOR) were not observed. Nevertheless, in the plantaris muscle, ET maintained high PGC1α levels. CONCLUSIONS: Thus, the ET capability to attenuate cardiac function during the transition from cardiac dysfunction to HF was accompanied by a prevention of skeletal muscle atrophy that did not occur via an increase in anabolic factors, but through anti-catabolic activity, presumably caused by PGC1α action. These findings indicate the therapeutic potential of aerobic ET to block HF-induced muscle atrophy by counteracting the increased catabolic state.