Skeletal Muscle Microvascular Dysfunction Manifests Early in Diabetic Cardiomyopathy

Aim: To perform a deep cardiac phenotyping of type II diabetes in a rat model, with the goal of gaining new insight into the temporality of microvascular dysfunction, cardiac dysfunction, and exercise intolerance at different stages of diabetes.Methods and Results: Diabetes was reproduced using a non-obese, diet-based, low-dose streptozotocin model in male rats (29 diabetic, 11 control). Time-course monitoring over 10 months was performed using echocardiography, treadmill exercise, photoacoustic perfusion imaging in myocardial and leg skeletal muscle, flow-mediated dilation, blood panel, and histology. Diabetic rats maintained a normal weight throughout. At early times (4 months), a non-significant reduction (30%) emerged in skeletal muscle perfusion and in exercise tolerance. At the same time, diabetic rats had a normal, slightly lower ejection fraction (63 vs. 71% control, p < 0.01), grade 1 diastolic dysfunction (E/A = 1.1 vs. 1.5, isovolumetric relaxation time = 34 vs. 27 ms; p < 0.01), mild systolic dysfunction (ejection time = 69 vs. 57 ms, isovolumetric contraction time = 21 vs. 17 ms; p < 0.01), and slightly enlarged left ventricle (8.3 vs. 7.6 mm diastole; p < 0.01). Diastolic dysfunction entered grade 3 at Month 8 (E/A = 1.7 vs. 1.3, p < 0.05). Exercise tolerance remained low in diabetic rats, with running distance declining by 60%; in contrast, control rats ran 60% farther by Month 5 (p < 0.05) and always remained above baseline. Leg muscle perfusion remained low in diabetic rats, becoming significantly lower than control by Month 10 (33% SO2 vs. 57% SO2, p < 0.01). Myocardial perfusion remained normal throughout. Femoral arterial reactivity was normal, but baseline velocity was 25% lower than control (p < 0.05). High blood pressure appeared late in diabetes (8 months). Histology confirmed absence of interstitial fibrosis, cardiomyocyte hypertrophy, or microvascular rarefaction in the diabetic heart. Rarefaction was also absent in leg skeletal muscle.Conclusion: Reduced skeletal muscle perfusion from microvascular dysfunction emerged early in diabetic rats, but myocardial perfusion remained normal throughout the study. At the same time, diabetic rats exhibited exercise intolerance and early cardiac dysfunction, in which changes related to heart failure with preserved ejection fraction (HFpEF) were seen. Importantly, skeletal muscle microvascular constrictionadvanced significantly before the late appearance of hypertension. HFpEF phenotypes such as cardiac hypertrophy, fibrosis, and rarefaction, which are typically associated with hypertension, were absent over the 10 month time-course of diabetes-related heart failure.

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Abstract 15025: Visceral Adiposity and Muscle Composition in Heart Failure With Preserved Ejection Fraction and Association With Exercise Tolerance

Circulation ◽

10.1161/circ.142.suppl_3.15025 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Wendy Ying ◽

Kavita Sharma ◽

Lisa R Yanek ◽

Dhananjay Vaidya ◽

Michael Schar ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Ejection Fraction ◽

Exercise Tolerance ◽

Nyha Class ◽

Well Being ◽

Liver Fat ◽

Exercise Intolerance ◽

Preserved Ejection Fraction ◽

Intermuscular Fat

Introduction: Visceral adipose tissue (AT) promotes inflammation and adverse metabolic changes that mediate disease progression in heart failure with preserved ejection fraction (HFpEF). Exercise intolerance is a hallmark of HFpEF, but little is known about its relation to the extent and distribution of AT. We characterized regional AT distribution in HFpEF patients and controls and analyzed associations with comorbidities and exercise tolerance. Methods: MRI was performed to quantify epicardial, liver, abdominal and thigh skeletal muscle AT. We assessed NYHA class, 6-minute walk distance (6MWD), and global well-being score (GWBS). Multivariable linear and logistic regression models were used, adjusted for age, sex, and body surface area. Results: We studied 55 HFpEF patients (41 women, mean age 67) and 33 controls (21 women, mean age 57). Epicardial AT (4.6 vs 3.2mm, p = 0.03), thigh intermuscular fat (11.0 vs 5.0cm 2 , p < 0.01) and liver fat fraction (FF) (6.4% vs 4.1%, p = 0.04) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal (443.9 vs 297.3 cm 2 , p = 0.03) and thigh (228.6 vs 112.3 cm 2 , p < 0.001) subcutaneous AT than men. Higher thigh intermuscular fat was associated with higher blood pressure (β [SE] 14.1 [3.3], p < 0.001) and diabetes (β [SE] 2.6 [1.1], p = 0.02), and liver FF was associated with chronic kidney disease (β [SE] 1.6 [0.6], p = 0.01). Higher thigh intramuscular fat was associated with both higher NYHA class and shorter 6MWD, and higher thigh intermuscular AT FF was associated with higher NYHA class ( Table ). Higher epicardial AT and liver FF were associated with lower GWBS. Conclusions: HFpEF patients have increased epicardial, liver, and skeletal muscle fat compared to controls out of proportion to their body size, and adiposity was associated with worse exercise intolerance in HFpEF. These results provide the basis for further investigation into regional AT distribution in relation to HFpEF symptoms and pathophysiology.

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Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training

Journal of Applied Physiology ◽

10.1152/japplphysiol.91067.2008 ◽

2009 ◽

Vol 106 (5) ◽

pp. 1631-1640 ◽

Cited By ~ 55

Author(s):

Aline V. N. Bacurau ◽

Maíra A. Jardim ◽

Julio C. B. Ferreira ◽

Luiz R. G. Bechara ◽

Carlos R. Bueno ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Skeletal Muscle ◽

Exercise Training ◽

Exercise Tolerance ◽

Muscular Atrophy ◽

Exercise Intolerance ◽

Muscle Morphology ◽

Sympathetic Hyperactivity ◽

Capillary Rarefaction

Sympathetic hyperactivity (SH) is a hallmark of heart failure (HF), and several lines of evidence suggest that SH contributes to HF-induced skeletal myopathy. However, little is known about the influence of SH on skeletal muscle morphology and metabolism in a setting of developing HF, taking into consideration muscles with different fiber compositions. The contribution of SH on exercise tolerance and skeletal muscle morphology and biochemistry was investigated in 3- and 7-mo-old mice lacking both α2A- and α2C-adrenergic receptor subtypes (α2A/α2CARKO mice) that present SH with evidence of HF by 7 mo. To verify whether exercise training (ET) would prevent skeletal muscle myopathy in advanced-stage HF, α2A/α2CARKO mice were exercised from 5 to 7 mo of age. At 3 mo, α2A/α2CARKO mice showed no signs of HF and preserved exercise tolerance and muscular norepinephrine with no changes in soleus morphology. In contrast, plantaris muscle of α2A/α2CARKO mice displayed hypertrophy and fiber type shift (IIA → IIX) paralleled by capillary rarefaction, increased hexokinase activity, and oxidative stress. At 7 mo, α2A/α2CARKO mice displayed exercise intolerance and increased muscular norepinephrine, muscular atrophy, capillary rarefaction, and increased oxidative stress. ET reestablished α2A/α2CARKO mouse exercise tolerance to 7-mo-old wild-type levels and prevented muscular atrophy and capillary rarefaction associated with reduced oxidative stress. Collectively, these data provide direct evidence that SH is a major factor contributing to skeletal muscle morphological changes in a setting of developing HF. ET prevented skeletal muscle myopathy in α2A/α2CARKO mice, which highlights its importance as a therapeutic tool for HF.

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Faculty Opinions recommendation of Fatigability, exercise intolerance, and abnormal skeletal muscle energetics in heart failure.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727807886.793538097 ◽

2017 ◽

Author(s):

Barry Borlaug

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Exercise Intolerance ◽

Muscle Energetics

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Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients

Scientific Reports ◽

10.1038/s41598-021-81736-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Takashi Yokota ◽

Shintaro Kinugawa ◽

Kagami Hirabayashi ◽

Mayumi Yamato ◽

Shingo Takada ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Skeletal Muscle ◽

Energy Metabolism ◽

Aerobic Capacity ◽

Plantar Flexion ◽

Exercise Intolerance ◽

Whole Body ◽

Resonance Spectroscopy ◽

Systemic Oxidative Stress

AbstractOxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

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Soothing the sleeping giant: improving skeletal muscle oxygen kinetics and exercise intolerance in HFpEF

Journal of Applied Physiology ◽

10.1152/japplphysiol.01127.2014 ◽

2015 ◽

Vol 119 (6) ◽

pp. 734-738 ◽

Cited By ~ 14

Author(s):

Satyam Sarma ◽

Benjamin D. Levine

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Oxygen Consumption ◽

Functional Capacity ◽

Oxidative Capacity ◽

Exercise Intolerance ◽

Aerobic Performance ◽

Muscle Oxygen ◽

Oxygen Kinetics ◽

Patients With Heart Failure

Patients with heart failure with preserved ejection fraction (HFpEF) have similar degrees of exercise intolerance and dyspnea as patients with heart failure with reduced EF (HFrEF). The underlying pathophysiology leading to impaired exertional ability in the HFpEF syndrome is not completely understood, and a growing body of evidence suggests “peripheral,” i.e., noncardiac, factors may play an important role. Changes in skeletal muscle function (decreased muscle mass, capillary density, mitochondrial volume, and phosphorylative capacity) are common findings in HFrEF. While cardiac failure and decreased cardiac reserve account for a large proportion of the decline in oxygen consumption in HFrEF, impaired oxygen diffusion and decreased skeletal muscle oxidative capacity can also hinder aerobic performance, functional capacity and oxygen consumption (V̇o2) kinetics. The impact of skeletal muscle dysfunction and abnormal oxidative capacity may be even more pronounced in HFpEF, a disease predominantly affecting the elderly and women, two demographic groups with a high prevalence of sarcopenia. In this review, we 1) describe the basic concepts of skeletal muscle oxygen kinetics and 2) evaluate evidence suggesting limitations in aerobic performance and functional capacity in HFpEF subjects may, in part, be due to alterations in skeletal muscle oxygen delivery and utilization. Improving oxygen kinetics with specific training regimens may improve exercise efficiency and reduce the tremendous burden imposed by skeletal muscle upon the cardiovascular system.

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Metabolic Myopathy in Heart Failure

Physiology ◽

10.1152/nips.01392.2002 ◽

2002 ◽

Vol 17 (5) ◽

pp. 191-196 ◽

Cited By ~ 5

Author(s):

Renée Ventura-Clapier ◽

Elvira De Sousa ◽

Vladimir Veksler

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Exercise Intolerance ◽

Metabolic Myopathy

Heart failure is a syndrome that also affects the periphery. Exercise intolerance and early fatigue seem to be linked in part to intrinsic alterations of skeletal muscle with decreases in both the production of ATP by mitochondria and the transfer of energy through the phosphotransfer kinases.

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Effect of diabetes and insulin treatment of diabetic rats on total RNA, poly(A)+ RNA, and mRNA in skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.1991.260.3.c409 ◽

1991 ◽

Vol 260 (3) ◽

pp. C409-C416 ◽

Cited By ~ 8

Author(s):

J. D. Kent ◽

S. R. Kimball ◽

L. S. Jefferson

Keyword(s):

Skeletal Muscle ◽

Ribosomal Rna ◽

Time Course ◽

Diabetic Rats ◽

In Vitro Translation ◽

Specific Gene ◽

Insulin Administration ◽

Tissue Mass ◽

Total Rna

We have assessed the time course of alterations in several biochemical parameters and expression of specific mRNAs in gastrocnemius muscle following both the induction of diabetes and the administration of insulin to diabetic rats. Muscle mass, total RNA, and total protein were reduced, whereas poly(A)+ RNA relative to total RNA was increased following the induction of diabetes. All the above parameters, with the exception of poly(A)+ RNA, were reciprocally and rapidly altered following administration of insulin to 3-day diabetic animals. These changes suggest that during the induction of diabetes 1) total cellular protein is reduced at a rate that is less than the reduction in gastrocnemius mass, whereas RNA is reduced at a rate 1.5 times the reduction in tissue mass, and 2) poly(A)+ RNA is elevated relative to total RNA. After insulin administration, there appears to be coordinate synthesis of both poly(A)+ RNA and ribosomal RNA, assuming 85% of total RNA is ribosomal. Therefore, we conclude that poly(A)+ RNA is more stable than ribosomal RNA during diabetes, whereas the amounts of poly(A)+ RNA and ribosomal RNA are increased at the same rates following insulin administration to diabetic animals. Analysis of expression of specific gene products over the same time course, as assessed by in vitro translation of total RNA followed by two-dimensional gel analysis, suggests that there are a few mRNAs that are very rapidly altered in response to insulin administration. The mRNAs that are altered demonstrate variable temporal patterns of either repression or full or transient expression. These rapid, but limited, alterations in gene expression may prove important in the development of the defects that occur in skeletal muscle in response to diabetes.

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Relation of microvascular dysfunction and exercise tolerance in patients with heart failure with preserved ejection fraction

Echocardiography ◽

10.1111/echo.14799 ◽

2020 ◽

Vol 37 (8) ◽

pp. 1192-1198 ◽

Cited By ~ 1

Author(s):

Ragab A. Mahfouz ◽

Mohammad Gouda ◽

Mohamed Abdelhamid

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Exercise Tolerance ◽

Microvascular Dysfunction ◽

Preserved Ejection Fraction ◽

Patients With Heart Failure

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Clinical Response to Personalized Exercise Therapy in Heart Failure Patients with Reduced Ejection Fraction Is Accompanied by Skeletal Muscle Histological Alterations

International Journal of Molecular Sciences ◽

10.3390/ijms20215514 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5514 ◽

Cited By ~ 2

Author(s):

Tatiana Lelyavina ◽

Victoria Galenko ◽

Oksana Ivanova ◽

Margarita Komarova ◽

Elena Ignatieva ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Ejection Fraction ◽

Clinical Response ◽

Exercise Therapy ◽

Left Ventricular ◽

Exercise Intolerance ◽

Left Ventricular Ejection ◽

Histological Alterations ◽

Before And After

Heart failure (HF) is associated with skeletal muscle wasting and exercise intolerance. This study aimed to evaluate the exercise-induced clinical response and histological alterations. One hundred and forty-four HF patients were enrolled. The individual training program was determined as a workload at or close to the lactate threshold (LT1); clinical data were collected before and after 12 weeks/6 months of training. The muscle biopsies from eight patients were taken before and after 12 weeks of training: histology analysis was used to evaluate muscle morphology. Most of the patients demonstrated a positive response after 12 weeks of the physical rehabilitation program in one or several parameters tested, and 30% of those showed improvement in all four of the following parameters: oxygen uptake (VO2) peak, left ventricular ejection fraction (LVEF), exercise tolerance (ET), and quality of life (QOL); the walking speed at LT1 after six months of training showed a significant rise. Along with clinical response, the histological analysis detected a small but significant decrease in both fiber and endomysium thickness after the exercise training course indicating the stabilization of muscle mechanotransduction system. Together, our data show that the beneficial effect of personalized exercise therapy in HF patients depends, at least in part, on the improvement in skeletal muscle physiological and biochemical performance.

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