Apoptosis of Skeletal Muscle Myofibers and Interstitial Cells in Experimental Heart Failure

doi:10.1006/jmcc.1998.0807

Journal of Molecular and Cellular Cardiology

Volume 30, Issue 11, November 1998, Pages 2449-2459

https://doi.org/10.1006/jmcc.1998.0807 Get rights and content

Abstract

Congestive heart failure (CHF) is characterized by a limb skeletal muscle myopathy with shift from the slow aerobic, fatigue resistant fibers, to the fast, anaerobic ones, and muscle bulk loss. Apoptosis (A) has been recently demonstrated to play a role in several cardiovascular diseases. Aim of the study: we have investigated the role of A in the skeletal muscle of the hindlimbs in an experimental model of CHF. Animals and methods: CHF was induced in 7 males 80–100 g Sprague-Dawley rats with 30 mg/kg monocrotaline. Five age and diet matched controls were also studied. The time course of A was also studied in additional animals at day 0, 17, 24 and 30 days. Results: At day 27 the electrophoretic analysis of myosin heavy chains (MHCs) demonstrated in the CHF rats the occurrence of a myopathy, with disappearance of slow MHC1 in the Tibialis Anterior (TA), and a significant shift from the slow to the fast isoforms in the soleus and EDL. Within situDNA nick-end labelling (TUNEL) we found in the TA of CHF animals a significantly higher number of TUNEL positive nuclei (0.43±0.24v0.08±0.02,P<0.02 and TUNEL positive myonuclei (0.031±0.012v0.0025±0.005,P<0.02). The time course of A showed a progressive rise in interstitial and myocyte A, accompanied by a drop in fibers cross-sectional area and muscle weight/body weight, that came out to be significant at 30 days. Western blot showed a lower expression of Bcl-2 at 27 days and a further drop at 30 days in the CHF rats. Double staining for TUNEL and antibody against anti-MHC2a and anti MHC2b+2x showed that A occurs non-selectively in all the myofiber types.βANP and Right Ventricle Mass/Volume (RVM/V) correlated significantly with total apoptotic nuclei. Conclusions: In CHF myofibers A can lead to muscle atrophy. Endothelial cells A may produce an imbalance in myofibres nutrition with relative ischemia that triggers the preferential synthesis of fast anaerobic myosin as an adaptive mechanism or alternatively induce myofibres death.

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However, it does provide insight in the temporal relationships between changes in capillarization and muscle mass or fiber characteristics in older adults. Animal studies have previously shown that endothelial apoptosis, capillary loss and/or impaired capillary function precede the decline in muscle mass (Vescovo et al., 1998; Wang et al., 2014). Furthermore, capillary proliferation seems to be a key factor for increasing muscle mass, as increasing capillarization is associated with increases in muscle mass in animals (Leiter et al., 2012).
Muscle fiber capillarization plays a fundamental role in the regulation of skeletal muscle mass maintenance. However, it remains unclear to what extent capillarization is related to various other skeletal muscle characteristics. In this study we determined whether muscle fiber capillarization is independently associated with measures of skeletal muscle mass, both on a whole-body and cellular level, and post-absorptive muscle protein synthesis rates in healthy older men.
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The present study provides further evidence that muscle fiber capillarization may be a critical factor in the regulation of skeletal muscle maintenance in healthy older men.
Stem cells transplantation positively modulates the heart-kidney cross talk in cardiorenal syndrome type II
2019, International Journal of Cardiology
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No statistically significant differences were seen for vWf and SMA differentiation for both hAFS (vWf 0.79 ± 0.39 cells/mm2, SMA 0.57 ± 0.56 cells/mm2) and rSVC-GFP groups (vWf 0.84 ± 0.32 cells/mm2, SMA 1.5 ± 1.05 cells/mm2, p = ns) even though there was a trend for higher differentiation potential for rSVC-GFP group (Fig. 3m). In this well characterized model of RV failure secondary to pulmonary hypertension [18,26] and systemic congestion, kidney injury occurred as demonstrated by the increased levels of sCreatinine and sNGAL. Clinical signs of congestion such as pleural effusion and ascites were present.
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Cell-treated rats showed a significant reduction of serum NGAL and Creatinine compared to CRSII. In both hAFS and rSVC-GFP group, kidney protein expression of NGAL was significantly lower than in CRSII (hAFS p = 0.036 and rSVC-GFP p < 0.0001) and similar to that of controls. In both hAFS and rSVC-GFP treated rats, we observed cell engraftment in the medulla and differentiation into tubular, endothelial and SMCs cells. Apoptosis was significantly decreased in cell-treated rats (hAFS 14.07 ± 1.38 and rSVC-GFP 12.67 ± 2.96 cells/mm²) and similar to controls (9.85 ± 2.1 cell/mm²). TUNEL-positive cells were mainly located in the kidney medulla. Pro-inflammatory cytokines were down regulated in cell-treated groups and similar to controls. In cell-treated rats, kidney and heart tissue NGAL was not complexed with MMP9 as in CRSII group, suggesting inhibition of MMPs activity.
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The data reported in this article are related to the paper entitle “Stem cells transplantation positively modulates the heart-kidney cross talk in Cardiorenal Syndrome Type II” (Vescovo et al., 2019), which analyzed the impact of stem cells injection in cardiorenal syndrome type II. The dataset contains detailed information on apoptosis and cytokines milieu modification after injection of c-Kit–selected human amniotic fluid stem cells (hAFS) or rats vascular progenitor cells (rSVC-GFP group) in an experimental model of CRSII. The data can be useful for clarifying the paracrine effects exerted by the injected cells.
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The aim of our study was to investigate whether stem cell (SC) therapy with human amniotic fluid stem cells (hAFS, fetal stem cells) and rat adipose tissue stromal vascular fraction cells–GFP positive cells (rSVC-GFP) was able to produce favorable effects on skeletal muscle (SM) remodeling in a well-established rat model of right heart failure (RHF).
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SC-treated (SCT) rats showed increased CSA (p < 0.004 vs MCT) similarly to controls with a reshift toward the slow MHC1 isoform. Apoptosis was significantly decreased (11.12. ± 8.8 cells/mm³ hAFS and 13.1 + 7.6 rSVC-GFP) (p < 0.001 vs MCT) and similar to controls (5.38 ± 3.0 cells/mm³).
RHF rats showed a dramatic reduction of satellite cells(MCT 0.2 ± 0.06% Pax7 native vs controls 2.60 ± 2.46%, p < 0.001), while SCT induced a repopulation of both native and SC derived satellite cells (p < 0.005).
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Many of the mechanisms leading to skeletal muscle wasting in COPD and heart failure are common to both conditions. These encompass neurohormonal activation and systemic inflammation.
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The mechanisms leading to muscle wastage include cytokine-triggered skeletal muscle apoptosis and ubiquitin-proteasomeand non-ubiquitin-dependent pathways.
The regulation of fiber type involves the growth hormone/insulin-like growth factor 1/calcineurin/transcriptional coactivator PGC1 cascade. The imbalance between protein synthesis and degradation plays an important role. Protein degradation can occur through ubiquitin-dependent and non-ubiquitin-dependent pathways. Very recently, two systems controlling ubiquitin-proteasome activation have been described: FOXO-ubiquitin ligase and NFkB ubiquitin ligase. These are triggered by TNFα and growth hormone/insulin-like growth factor 1.
Moreover, apoptosis, which is triggered by tumor necrosis factor α, plays an important role. Another mechanism acting on muscle wastage is malnutrition, with an imbalance between catabolic and anabolic factors toward the catabolic component. Catabolism is also worsened by the activation of the adrenergic system and alteration of the cortisol/DEHA ratio toward cortisol production. Sarcomeric protein oxidation and its consequent contractile impairment can be another cause of skeletal muscle dysfunction in CHF.

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^f1: Please address all correspondence to: Giorgio Vescovo, Internal Medicine I, Ospedale Civile, SS Giovanni e Paolo, Castello, 30100 Venice, Italy.

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Regular ArticleApoptosis of Skeletal Muscle Myofibers and Interstitial Cells in Experimental Heart Failure

Abstract

Regular Article
Apoptosis of Skeletal Muscle Myofibers and Interstitial Cells in Experimental Heart Failure