RESUMEN
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.
Asunto(s)
Insuficiencia Cardíaca , Trasplante de Corazón , Calidad de Vida , Humanos , Consenso , Europa (Continente) , Ejercicio Físico , Insuficiencia Cardíaca/rehabilitación , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón/efectos adversos , Sociedades MédicasRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is characterized by biomechanically dysfunctional cardiomyocytes. Underlying cellular changes include perturbed myocardial titin expression and titin hypophosphorylation leading to titin filament stiffening. Beside these well-studied alterations at the cardiomyocyte level, exercise intolerance is another hallmark of HFpEF caused by molecular alterations in skeletal muscle (SKM). Currently, there is a lack of data regarding titin modulation in the SKM of HFpEF. Therefore, the aim of the present study was to analyze molecular alterations in limb SKM (tibialis anterior (TA)) and in the diaphragm (Dia), as a more central SKM, with a focus on titin, titin phosphorylation, and contraction-regulating proteins. This study was performed with muscle tissue, obtained from 32-week old female ZSF-1 rats, an established a HFpEF rat model. Our results showed a hyperphosphorylation of titin in limb SKM, based on enhanced phosphorylation at the PEVK region, which is known to lead to titin filament stiffening. This hyperphosphorylation could be reversed by high-intensity interval training (HIIT). Additionally, a negative correlation occurring between the phosphorylation state of titin and the muscle force in the limb SKM was evident. For the Dia, no alterations in the phosphorylation state of titin could be detected. Supported by data of previous studies, this suggests an exercise effect of the Dia in HFpEF. Regarding the expression of contraction regulating proteins, significant differences between Dia and limb SKM could be detected, supporting muscle atrophy and dysfunction in limb SKM, but not in the Dia. Altogether, these data suggest a correlation between titin stiffening and the appearance of exercise intolerance in HFpEF, as well as a differential regulation between different SKM groups.
Asunto(s)
Conectina , Diafragma , Modelos Animales de Enfermedad , Insuficiencia Cardíaca , Músculo Esquelético , Animales , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/patología , Ratas , Diafragma/metabolismo , Diafragma/fisiopatología , Diafragma/patología , Conectina/metabolismo , Fosforilación , Femenino , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Músculo Esquelético/patología , Volumen Sistólico , Contracción Muscular , Condicionamiento Físico Animal , Proteínas Musculares/metabolismoRESUMEN
[Figure: see text].
Asunto(s)
Diafragma/metabolismo , Insuficiencia Cardíaca/metabolismo , Mitocondrias Musculares/metabolismo , Debilidad Muscular/metabolismo , Calcio/metabolismo , Diafragma/fisiopatología , Diafragma/ultraestructura , Femenino , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/patología , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/ultraestructura , Proteínas Musculares/metabolismo , Debilidad Muscular/etiología , Debilidad Muscular/patología , NADPH Oxidasas/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Hind limb ischemia (HLI) is the most severe form of peripheral arterial disease, associated with a substantial reduction of limb blood flow that impairs skeletal muscle homeostasis to promote functional disability. The molecular regulators of HLI-induced muscle perturbations remain poorly defined. This study investigated whether changes in the molecular catabolic-autophagy signaling network were linked to temporal remodeling of skeletal muscle in HLI. HLI was induced in mice via hindlimb ischemia (femoral artery ligation) and confirmed by Doppler echocardiography. Experiments were terminated at time points defined as early- (7 days; n = 5) or late- (28 days; n = 5) stage HLI. Ischemic and nonischemic (contralateral) limb muscles were compared. Ischemic versus nonischemic muscles demonstrated overt remodeling at early-HLI but normalized at late-HLI. Early-onset fiber atrophy was associated with excessive autophagy signaling in ischemic muscle; protein expression increased for Beclin-1, LC3, and p62 (P < 0.05) but proteasome-dependent markers were reduced (P < 0.05). Mitophagy signaling increased in early-stage HLI that aligned with an early and sustained loss of mitochondrial content (P < 0.05). Upstream autophagy regulators, Sestrins, showed divergent responses during early-stage HLI (Sestrin2 increased while Sestrin1 decreased; P < 0.05) in parallel to increased AMP-activated protein kinase (AMPK) phosphorylation (P < 0.05) and lower antioxidant enzyme expression. No changes were found in markers for mechanistic target of rapamycin complex 1 signaling. These data indicate that early activation of the sestrin-AMPK signaling axis may regulate autophagy to stimulate rapid and overt muscle atrophy in HLI, which is normalized within weeks and accompanied by recovery of muscle mass. A complex interplay between Sestrins to regulate autophagy signaling during early-to-late muscle remodeling in HLI is likely.
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Miembro Posterior , Isquemia , Músculo Esquelético , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Modelos Animales de Enfermedad , Arteria Femoral/metabolismo , Miembro Posterior/irrigación sanguínea , Miembro Posterior/metabolismo , Isquemia/metabolismo , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , SestrinasRESUMEN
KEY POINTS: Heart failure is characterised by limb and respiratory muscle impairments that limit functional capacity and quality of life. However, compared with heart failure with reduced ejection fraction (HFrEF), skeletal muscle alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly explored. Here we report that obese-HFpEF induces multiple skeletal muscle alterations in the rat hindlimb, including impaired muscle mechanics related to shortening velocity, fibre atrophy, capillary loss, and an impaired blood flow response to contractions that implies a perfusive oxygen delivery limitation. We also demonstrate that obese-HFpEF is characterised by diaphragmatic alterations similar to those caused by denervation - atrophy in Type IIb/IIx (fast/glycolytic) fibres and hypertrophy in Type I (slow/oxidative) fibres. These findings extend current knowledge in HFpEF skeletal muscle physiology, potentially underlying exercise intolerance, which may facilitate future therapeutic approaches. ABSTRACT: Peripheral skeletal muscle and vascular alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly identified, with limited therapeutic targets. This study used a cardiometabolic obese-HFpEF rat model to comprehensively phenotype skeletal muscle mechanics, blood flow, microvasculature and fibre atrophy. Lean (n = 8) and obese-HFpEF (n = 8) ZSF1 rats were compared. Skeletal muscles (soleus and diaphragm) were assessed for in vitro contractility (isometric and isotonic properties) alongside indices of fibre-type cross-sectional area, myosin isoform, and capillarity, and estimated muscle PO2 . In situ extensor digitorum longus (EDL) contractility and femoral blood flow were assessed. HFpEF soleus demonstrated lower absolute maximal force by 22%, fibre atrophy by 24%, a fibre-type shift from I to IIa, and a 17% lower capillary-to-fibre ratio despite increased capillary density (all P < 0.05) with preserved muscle PO2 (P = 0.115) and isometric specific force (P > 0.05). Soleus isotonic properties (shortening velocity and power) were impaired by up to 17 and 22%, respectively (P < 0.05), while the magnitude of the exercise hyperaemia was attenuated by 73% (P = 0.012) in line with higher muscle fatigue by 26% (P = 0.079). Diaphragm alterations (P < 0.05) included Type IIx fibre atrophy despite Type I/IIa fibre hypertrophy, with increased indices of capillarity alongside preserved contractile properties during isometric, isotonic, and cyclical contractions. In conclusion, obese-HFpEF rats demonstrated blunted skeletal muscle blood flow during contractions in parallel to microvascular structural remodelling, fibre atrophy, and isotonic contractile dysfunction in the locomotor muscles. In contrast, diaphragm phenotype remained well preserved. This study identifies numerous muscle-specific impairments that could exacerbate exercise intolerance in obese-HFpEF.
Asunto(s)
Insuficiencia Cardíaca , Animales , Contracción Muscular , Músculo Esquelético , Obesidad , Calidad de Vida , Ratas , Volumen SistólicoRESUMEN
BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by blunting of the positive relationship between heart rate and left ventricular (LV) contractility known as the force-frequency relationship (FFR). We have previously described that tailoring the rate-response programming of cardiac implantable electronic devices in patients with HFrEF on the basis of individual noninvasive FFR data acutely improves exercise capacity. We aimed to examine whether using FFR data to tailor heart rate response in patients with HFrEF with cardiac implantable electronic devices favorably influences exercise capacity and LV function 6 months later. METHODS: We conducted a single-center, double-blind, randomized, parallel-group trial in patients with stable symptomatic HFrEF taking optimal guideline-directed medical therapy and with a cardiac implantable electronic device (cardiac resynchronization therapy or implantable cardioverter-defibrillator). Participants were randomized on a 1:1 basis between tailored rate-response programming on the basis of individual FFR data and conventional age-guided rate-response programming. The primary outcome measure was change in walk time on a treadmill walk test. Secondary outcomes included changes in LV systolic function, peak oxygen consumption, and quality of life. RESULTS: We randomized 83 patients with a mean±SD age 74.6±8.7 years and LV ejection fraction 35.2±10.5. Mean change in exercise time at 6 months was 75.4 (95% CI, 23.4 to 127.5) seconds for FFR-guided rate-adaptive pacing and 3.1 (95% CI, -44.1 to 50.3) seconds for conventional settings (analysis of covariance; P=0.044 between groups) despite lower peak mean±SD heart rates (98.6±19.4 versus 112.0±20.3 beats per minute). FFR-guided heart rate settings had no adverse effect on LV structure or function, whereas conventional settings were associated with a reduction in LV ejection fraction. CONCLUSIONS: In this phase II study, FFR-guided rate-response programming determined using a reproducible, noninvasive method appears to improve exercise time and limit changes to LV function in people with HFrEF and cardiac implantable electronic devices. Work is ongoing to confirm our findings in a multicenter setting and on longer-term clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02964650.
Asunto(s)
Dispositivos de Terapia de Resincronización Cardíaca , Terapia de Resincronización Cardíaca , Desfibriladores Implantables , Cardioversión Eléctrica/instrumentación , Tolerancia al Ejercicio , Insuficiencia Cardíaca/terapia , Frecuencia Cardíaca , Volumen Sistólico , Función Ventricular Izquierda , Anciano , Anciano de 80 o más Años , Terapia de Resincronización Cardíaca/efectos adversos , Método Doble Ciego , Cardioversión Eléctrica/efectos adversos , Inglaterra , Femenino , Estado Funcional , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Recuperación de la Función , Factores de Tiempo , Resultado del Tratamiento , Prueba de PasoRESUMEN
Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. This review discusses recent progress in understanding the molecular pathways involved in regulating skeletal muscle wasting with a focus on pro-catabolic factors, in particular, the ubiquitin-proteasome system and its activating muscle-specific E3 ligase RING-finger protein 1 (MuRF1). Mechanistic progress has provided the opportunity to design experimental therapeutic concepts that may affect the ubiquitin-proteasome system and prevent subsequent muscle wasting, with novel advances made in regards to nutritional supplements, nuclear factor kappa-light-chain-enhancer of activated B cells (NFB) inhibitors, myostatin antibodies, ß2 adrenergic agonists, and small-molecules interfering with MuRF1, which all emerge as a novel in vivo treatment strategies for muscle wasting.
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Terapia Molecular Dirigida , Atrofia Muscular/tratamiento farmacológico , Animales , Humanos , Proteínas Musculares/antagonistas & inhibidores , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas de Motivos Tripartitos/antagonistas & inhibidores , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is underpinned by detrimental skeletal muscle alterations that contribute to disease severity, yet underlying mechanisms and therapeutic treatments remain poorly established. This study used a nonhuman animal model of HFpEF to better understand whether skeletal muscle abnormalities were (1) fiber-type specific and (2) reversible by various exercise training regimes. METHODS AND RESULTS: Lean control rats were compared with obese ZSF1 rats at 20 weeks and then 8 weeks after sedentary, high-intensity interval training, or moderate continuous treadmill exercise. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were assessed for fiber size, capillarity, glycolytic metabolism, autophagy, and contractile function. HFpEF reduced fiber size and capillarity by 20%-50% (P < .05) in both soleus and EDL, but these effects were not reversed by endurance training. In contrast, both endurance training regimes in HFpEF attenuated the elevated lactate dehydrogenase activity observed in the soleus. Autophagy was down-regulated in EDL and up-regulated in soleus (P < .05), with no influence of endurance training. HFpEF impaired contractile forces of both muscles by â¼20% (P < .05), and these were not reversed by training. CONCLUSIONS: Obesity-related HFpEF was associated with detrimental structural, cellular, and functional alterations to both slow-oxidative and fast-glycolytic skeletal muscles that could not be reversed by endurance training.
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Insuficiencia Cardíaca/rehabilitación , Contracción Muscular/fisiología , Músculo Esquelético/patología , Estrés Oxidativo , Condicionamiento Físico Animal/métodos , Volumen Sistólico/fisiología , Animales , Autofagia , Modelos Animales de Enfermedad , Terapia por Ejercicio , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Hidroliasas/metabolismo , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Ratas , Ratas ZuckerRESUMEN
Hypertension is a key risk factor for heart failure, with the latter characterized by diaphragm muscle weakness that is mediated in part by increased oxidative stress. In the present study, we used a deoxycorticosterone acetate (DOCA)-salt mouse model to determine whether hypertension could independently induce diaphragm dysfunction and further investigated the effects of high-intensity interval training (HIIT). Sham-treated (n = 11), DOCA-salt-treated (n = 11), and DOCA-salt+HIIT-treated (n = 15) mice were studied over 4 wk. Diaphragm contractile function, protein expression, enzyme activity, and fiber cross-sectional area and type were subsequently determined. Elevated blood pressure confirmed hypertension in DOCA-salt mice independent of HIIT (P < 0.05). Diaphragm forces were impaired by â¼15-20% in DOCA-salt vs. sham-treated mice (P < 0.05), but this effect was prevented after HIIT. Myosin heavy chain (MyHC) protein expression tended to decrease (â¼30%; P = 0.06) in DOCA-salt vs. sham- and DOCA-salt+HIIT mice, whereas oxidative stress increased (P < 0.05). Enzyme activity of NADPH oxidase was higher, but superoxide dismutase was lower, with MyHC oxidation elevated by â¼50%. HIIT further prevented direct oxidant-mediated diaphragm contractile dysfunction (P < 0.05) after a 30 min exposure to H2O-2 (1 mM). Our data suggest that hypertension induces diaphragm contractile dysfunction via an oxidant-mediated mechanism that is prevented by HIIT.-Bowen, T. S., Eisenkolb, S., Drobner, J., Fischer, T., Werner, S., Linke, A., Mangner, N., Schuler, G., Adams, V. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice.
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Diafragma/patología , Entrenamiento de Intervalos de Alta Intensidad , Debilidad Muscular/prevención & control , Oxidantes/metabolismo , Condicionamiento Físico Animal/fisiología , Animales , Fenómenos Fisiológicos Cardiovasculares , Desoxicorticosterona/administración & dosificación , Desoxicorticosterona/farmacología , Hipertensión , Masculino , Ratones , Ratones Endogámicos C57BL , Mineralocorticoides/administración & dosificación , Mineralocorticoides/farmacología , Mitocondrias/fisiología , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Debilidad Muscular/metabolismo , Estrés OxidativoRESUMEN
Time-resolved near-infrared spectroscopy (TRS-NIRS) allows absolute quantitation of deoxygenated haemoglobin and myoglobin concentration ([HHb]) in skeletal muscle. We recently showed that the spatial distribution of peak [HHb] within the quadriceps during moderate-intensity cycling is reduced with progressive hypoxia and this is associated with impaired aerobic energy provision. We therefore aimed to determine whether reduced spatial distribution of skeletal muscle [HHb] was associated with impaired aerobic energy transfer during exhaustive ramp-incremental exercise in hypoxia. Seven healthy men performed ramp-incremental cycle exercise (20 W/min) to exhaustion at 3 fractional inspired O2 concentrations (FIO2): 0.21, 0.16, 0.12. Pulmonary O2 uptake ([Formula: see text]) was measured using a flow meter and gas analyser system. Lactate threshold (LT) was estimated non-invasively. Absolute muscle deoxygenation was quantified by multichannel TRS-NIRS from the rectus femoris and vastus lateralis (proximal and distal regions). [Formula: see text] and LT were progressively reduced (p<0.05) with hypoxia. There was a significant effect (p<0.05) of FIO2 on [HHb] at baseline, LT, and peak. However the spatial variance of [HHb] was not different between FIO2 conditions. Peak total Hb ([Hbtot]) was significantly reduced between FIO2 conditions (p<0.001). There was no association between reductions in the spatial distribution of skeletal muscle [HHb] and indices of aerobic energy transfer during ramp-incremental exercise in hypoxia. While regional [HHb] quantified by TRS-NIRS at exhaustion was greater in hypoxia, the spatial distribution of [HHb] was unaffected. Interestingly, peak [Hbtot] was reduced at the tolerable limit in hypoxia implying a vasodilatory reserve may exist in conditions with reduced FIO2.
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Ejercicio Físico , Hipoxia/metabolismo , Músculo Esquelético/metabolismo , Oxígeno/metabolismo , Adulto , Hemoglobinas/análisis , Humanos , Masculino , Consumo de Oxígeno , Espectroscopía Infrarroja CortaRESUMEN
During constant-power high-intensity exercise, the expected increase in oxygen uptake (VÌO2) is supplemented by a VÌO2 slow component (VÌO2 sc ), reflecting reduced work efficiency, predominantly within the locomotor muscles. The intracellular source of inefficiency is postulated to be an increase in the ATP cost of power production (an increase in P/W). To test this hypothesis, we measured intramuscular ATP turnover with (31)P magnetic resonance spectroscopy (MRS) and whole-body VÌO2 during moderate (MOD) and heavy (HVY) bilateral knee-extension exercise in healthy participants (n = 14). Unlocalized (31)P spectra were collected from the quadriceps throughout using a dual-tuned ((1)H and (31)P) surface coil with a simple pulse-and-acquire sequence. Total ATP turnover rate (ATPtot) was estimated at exercise cessation from direct measurements of the dynamics of phosphocreatine (PCr) and proton handling. Between 3 and 8 min during MOD, there was no discernable VÌO2 sc (mean ± SD, 0.06 ± 0.12 l min(-1)) or change in [PCr] (30 ± 8 vs. 32 ± 7 mm) or ATPtot (24 ± 14 vs. 17 ± 14 mm min(-1); each P = n.s.). During HVY, the VÌO2 sc was 0.37 ± 0.16 l min(-1) (22 ± 8%), [PCr] decreased (19 ± 7 vs. 18 ± 7 mm, or 12 ± 15%; P < 0.05) and ATPtot increased (38 ± 16 vs. 44 ± 14 mm min(-1), or 26 ± 30%; P < 0.05) between 3 and 8 min. However, the increase in ATPtot (ΔATPtot) was not correlated with the VÌO2 sc during HVY (r(2) = 0.06; P = n.s.). This lack of relationship between ΔATPtot and VÌO2 sc , together with a steepening of the [PCr]-VÌO2 relationship in HVY, suggests that reduced work efficiency during heavy exercise arises from both contractile (P/W) and mitochondrial sources (the O2 cost of ATP resynthesis; P/O).
Asunto(s)
Adenosina Trifosfato/metabolismo , Ejercicio Físico/fisiología , Músculo Esquelético/metabolismo , Adulto , Anaerobiosis , Femenino , Glucólisis , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Mitocondrias Musculares/metabolismo , Contracción Muscular/fisiología , Fosforilación Oxidativa , Oxígeno/fisiología , Consumo de Oxígeno/fisiología , Fosfocreatina/metabolismo , Intercambio Gaseoso Pulmonar/fisiología , Adulto JovenRESUMEN
AIMS: Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF. METHODS AND RESULTS: Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment. CONCLUSIONS: Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.
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Insuficiencia Cardíaca , Músculo Esquelético , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Volumen Sistólico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Masculino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/metabolismo , Humanos , Volumen Sistólico/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Animales , Ratones , Persona de Mediana Edad , Anciano , BiopsiaRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is a major clinical problem, with limited treatments. HFpEF is characterized by a distinct, but poorly understood, skeletal muscle pathology, which could offer an alternative therapeutic target. In a rat model, we identified impaired myonuclear accretion as a mechanism for low myofiber growth in HFpEF following resistance exercise. Acute caloric restriction rescued skeletal muscle pathology in HFpEF, whereas cardiac therapies had no effect. Mechanisms regulating myonuclear accretion were dysregulated in patients with HFpEF. Overall, these findings may have widespread implications in HFpEF, indicating combined dietary with exercise interventions as a beneficial approach to overcome skeletal muscle pathology.
RESUMEN
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus.
RESUMEN
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.
RESUMEN
It remains unclear whether an overshoot in skeletal muscle deoxygenation (HHb; reflecting a microvascular kinetic mismatch of O2 delivery to consumption) contributes to the slowed adjustment of oxidative energy provision at the onset of exercise. We progressively reduced the fractional inspired O2 concentration (F(I,O2)) to investigate the relationship between slowed pulmonary O2 uptake (V(O2)) kinetics and the dynamics and spatial distribution of absolute[HHb]. Seven healthy men performed 8 min cycling transitions during normoxia (F(I,O2) = 0.21),moderate hypoxia (F(I,O2) = 0.16) and severe hypoxia (F(I,O2)= 0.12). V(O2) uptake was measured using a flowmeter and gas analyser system. Absolute [HHb] was quantified by multichannel,time-resolved near-infrared spectroscopy from the rectus femoris and vastus lateralis (proximal and distal regions), and corrected for adipose tissue thickness. The phase II V(O2) time constant was slowed (P <0.05) as F(I,O2) decreased (normoxia, 17 ± 3 s;moderate hypoxia, 22 ± 4 s; and severe hypoxia, 29 ± 9 s). The [HHb] overshoot was unaffected by hypoxia, but the transient peak [HHb] increased with the reduction in F(I,O2) (P <0.05). Slowed V(O2) kinetics in hypoxia were positively correlated with increased peak [HHb] in the transient (r(2) = 0.45; P <0.05), but poorly related to the [HHb] overshoot. A reduction of spatial heterogeneity in peak [HHb]was inversely correlated with slowed V(O2) kinetics (r(2) = 0.49; P <0.05). These data suggest that aerobic energy provision at the onset of exercise may be limited by the following factors: (i) the absolute ratio (i.e. peak [HHb]) rather than the kinetic ratio (i.e. [HHb] overshoot) of microvascular O2 delivery to consumption; and (ii) a reduced spatial distribution in the ratio of microvascular O2 delivery to consumption across the muscle.
Asunto(s)
Ejercicio Físico/fisiología , Hipoxia/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxígeno/fisiología , Hemoglobinas/metabolismo , Humanos , Masculino , Músculo Esquelético/irrigación sanguínea , Oxígeno/metabolismo , Músculo Cuádriceps/metabolismo , Adulto JovenRESUMEN
This review highlights some established and some more contemporary mechanisms responsible for heart failure (HF)-induced skeletal muscle wasting and weakness. We first describe the effects of HF on the relationship between protein synthesis and degradation rates, which determine muscle mass, the involvement of the satellite cells for continual muscle regeneration, and changes in myofiber calcium homeostasis linked to contractile dysfunction. We then highlight key mechanistic effects of both aerobic and resistance exercise training on skeletal muscle in HF and outline its application as a beneficial treatment. Overall, HF causes multiple impairments related to autophagy, anabolic-catabolic signaling, satellite cell proliferation, and calcium homeostasis, which together promote fiber atrophy, contractile dysfunction, and impaired regeneration. Although both wasting and weakness are partly rescued by aerobic and resistance exercise training in HF, the effects of satellite cell dynamics remain poorly explored.
Asunto(s)
Calcio , Insuficiencia Cardíaca , Humanos , Calcio/metabolismo , Atrofia Muscular/terapia , Atrofia Muscular/etiología , Músculo Esquelético/metabolismo , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/metabolismo , Ejercicio Físico , RegeneraciónRESUMEN
Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA-binding protein 43 (TDP-43) and promotes aggregation of TDP-43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro-atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.