Skeletal muscle ouabain binding sites are reduced in rats with chronic heart failure

2002 ◽  
Vol 92 (6) ◽  
pp. 2326-2334 ◽  
Author(s):  
Timothy I. Musch ◽  
Swen Wolfram ◽  
K. Sue Hageman ◽  
Joel G. Pickar
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Chronic Heart Failure ◽  
Oxygen Uptake ◽  
Binding Sites ◽  
Ouabain Binding ◽  
High Affinity ◽  
Lv Dysfunction ◽  
Run Time ◽  
Fast Twitch

Intrinsic skeletal muscle abnormalities decrease muscular endurance in chronic heart failure (CHF). In CHF patients, the number of skeletal muscle Na+-K+ pumps that have a high affinity for ouabain (i.e., the concentration of [3H]ouabain binding sites) is reduced, and this reduction is correlated with peak oxygen uptake. The present investigation determined whether the concentration of skeletal muscle [3H]ouabain binding sites found during CHF is related to 1) severity of the disease state, 2) muscle fiber type composition, and/or 3) endurance capacity. Four muscles were chosen that represented slow-twitch oxidative (SO), fast-twitch oxidative glycolytic (FOG), fast-twitch glycolytic (FG), and mixed fiber types. Measurements were obtained 8–10 wk postsurgery in 23 myocardial infarcted (MI) and 18 sham-operated control (sham) rats. Eighteen rats had moderate left ventricular (LV) dysfunction [LV end-diastolic pressure (LVEDP) < 20 mmHg], and five had severe LV dysfunction (LVEDP > 20 mmHg). Rats with severe LV dysfunction had significant pulmonary congestion and were likely in a chronic state of compensated congestive failure as indicated by an approximately twofold increase in both lung and right ventricle weight. Run time to fatigue and maximal oxygen uptake (V˙o 2 max) were significantly reduced (↓39 and ↓28%, respectively) in the rats with severe LV dysfunction and correlated with the magnitude of LV dysfunction as indicated by LVEDP (run time: r = 0.60, n = 21, P < 0.01 and V˙o 2 max: r = 0.93, n = 13, P < 0.01). In addition, run time to fatigue was significantly correlated withV˙o 2 max ( r = 0.87, n = 15, P < 0.01). The concentration of [3H]ouabain binding sites (Bmax) was significantly reduced (21–28%) in the three muscles comprised primarily of oxidative fibers [soleus: 259 ± 14 vs. 188 ± 17; plantaris: 295 ± 17 vs. 229 ± 18; red portion of gastrocnemius: 326 ± 17 vs. 260 ± 14 pmol/g wet tissue wt]. In addition, Bmax was significantly correlated withV˙o 2 max (soleus: r = 0.54, n = 15, P < 0.05; plantaris: r = 0.59, n = 15, P < 0.05; red portion of gastrocnemius: r = 0.65, n = 15, P < 0.01). These results suggest that downregulation of Na+-K+ pumps that possess a high affinity for ouabain in oxidative skeletal muscle may play an important role in the exercise intolerance that attends severe LV dysfunction in CHF.

Decreased [3H]ouabain binding sites in skeletal muscle of rats with chronic heart failure

1997 ◽  
Vol 83 (1) ◽  
pp. 323-323 ◽  
Author(s):  
Joel G. Pickar ◽  
John P. Mattson ◽  
Steve Lloyd ◽  
Timothy I. Musch
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Chronic Heart Failure ◽  
Exercise Capacity ◽  
Binding Sites ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Body Weight Ratio ◽  
Ouabain Binding

Pickar, Joel G., John P. Mattson, Steve Lloyd, and Timothy I. Musch. Decreased [3H]ouabain binding sites in skeletal muscle of rats with chronic heart failure. J. Appl. Physiol. 83(1): 323–329, 1997.—Abnormalities intrinsic to skeletal muscle are thought to contribute to decrements in exercise capacity found in individuals with chronic heart failure (CHF). Na+-K+-adenosinetriphosphatase (the Na+ pump) is essential for maintaining muscle excitability and contractility. Therefore, we investigated the possibility that the number and affinity of Na+ pumps in locomotor muscles of rats with CHF are decreased. Myocardial infarction (MI) was induced in 8 rats, and a sham operation was performed in 12 rats. The degree of CHF was assessed ∼180 days after surgery. Soleus and plantaris muscles were harvested, and Na+pumps were quantified by using a [3H]ouabain binding assay. At the time of muscle harvest, MI and sham-operated rats were similar in age (458 ± 54 vs. 447 ± 34 days old, respectively). Compared with their sham-operated counterparts, MI rats had a significant amount of heart failure, right ventricular-to-body weight ratio was greater (48%), and the presence of pulmonary congestion was suggested by an elevated lung-to-body weight ratio (29%). Left ventricular end-diastolic pressure was significantly increased in the MI rats (11 ± 1 mmHg) compared with the sham-operated controls (1 ± 1 mmHg). In addition, mean arterial blood pressure was lower in the MI rats compared with their control counterparts. [3H]ouabain binding sites were reduced 18% in soleus muscle (136 ± 12 vs. 175 ± 13 pmol/g wet wt, MI vs. sham, respectively) and 22% in plantaris muscle (119 ± 12 vs. 147 ± 8 pmol/g wet wt, MI vs. sham, respectively). The affinity of these [3H]ouabain binding sites was similar for the two groups. The relationship between the reduction in Na+ pump number and the reduced exercise capacity in individuals with CHF remains to be determined.

scholarly journals Manifested skeletal muscle abnormalities in fast‐twitch, glycolytic myofibers in mice of chronic heart failure

2006 ◽  
Vol 20 (4) ◽  
Author(s):  
Ping Li ◽  
Richard E. Waters ◽  
Shelley I. Odronic ◽  
Lan Mao ◽  
Brian H. Annex ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Chronic Heart Failure ◽  
Fast Twitch

Training-induced changes in skeletal muscle Na+-K+ pump number and isoform expression in rats with chronic heart failure

2003 ◽  
Vol 94 (6) ◽  
pp. 2225-2236 ◽  
Author(s):  
Bryan Helwig ◽  
Katherine M. Schreurs ◽  
Joslyn Hansen ◽  
K. Sue Hageman ◽  
Michael G. Zbreski ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Chronic Heart Failure ◽  
Exercise Training ◽  
Left Ventricular ◽  
Β Subunit ◽  
Severe Left Ventricular Dysfunction ◽  
Subunit Expression ◽  
Run Time ◽  
Isoform Expression

The mechanisms responsible for the decrements in exercise performance in chronic heart failure (CHF) remain poorly understood, but it has been suggested that sarcolemmal alterations could contribute to the early onset of muscular fatigue. Previously, our laboratory demonstrated that the maximal number of ouabain binding sites (Bmax) is reduced in the skeletal muscle of rats with CHF (Musch TI, Wolfram S, Hageman KS, and Pickar JG. J Appl Physiol 92: 2326–2334, 2002). These reductions may coincide with changes in the Na+-K+-ATPase isoform (α and β) expression. In the present study, we tested the hypothesis that reductions in Bmax would coincide with alterations in the α- and β-subunit expression of the sarcolemmal Na+-K+-ATPase of rats with CHF. Moreover, we tested the hypothesis that exercise training would increase Bmax along with producing significant changes in α- and β-subunit expression. Rats underwent a sham operation (sham; n = 10) or a surgically induced myocardial infarction followed by random assignment to either a control (MI; n = 16) or exercise training group (MI-T; n = 16). The MI-T rats performed exercise training (ET) for 6–8 wk. Hemodynamic indexes demonstrated that MI and MI-T rats suffered from severe left ventricular dysfunction and congestive CHF. Maximal oxygen uptake (V˙o 2 max) and endurance capacity (run time to fatigue) were reduced in MI rats compared with sham. Bmax in the soleus and plantaris muscles and the expression of the α2-isoform of the Na+-K+-ATPase in the red portion of the gastrocnemius (gastrocnemiusred) muscle were reduced in MI rats. After ET, V˙o 2 max and run time to fatigue were increased in the MI-T group of rats. This coincided with increases in soleus and plantaris Bmax and the expression of the α2-isoform in the gastrocnemiusred muscle. In addition, the expression of the β2-isoform of the gastrocnemiusred muscle was increased in the MI-T rats compared with their sedentary counterparts. This study demonstrates that CHF-induced alterations in skeletal muscle Na+-K+-ATPase, including Bmax and isoform expression, can be partially reversed by ET.

Age-associated differential expression of Na+-K+-ATPase subunit isoforms in skeletal muscles of F-344/BN rats

1999 ◽  
Vol 87 (3) ◽  
pp. 1132-1140 ◽  
Author(s):  
Xiwu Sun ◽  
Murali Nagarajan ◽  
Philip W. Beesley ◽  
Yuk-Chow Ng
Keyword(s):  
Skeletal Muscle ◽  
Atpase Activity ◽  
Binding Sites ◽  
Skeletal Muscles ◽  
Brown Norway ◽  
Muscle Type ◽  
Ouabain Binding ◽  
High Affinity ◽  
Old Rats ◽  
Subunit Isoforms

Skeletal muscle expresses multiple isoforms of the Na+-K+-ATPase. Their expression has been shown to be differentially regulated under pathophysiological conditions. In addition, previous studies suggest possible age-dependent alterations in Na+-K+pump function. The present study tests the hypothesis that advancing age is associated with altered Na+-K+-ATPase enzyme activity and isoform-specific changes in expression of the enzyme subunits. Red and white gastrocnemius (Gast) as well as soleus muscles of male Fischer 344/Brown Norway (F-344/BN) rats at 6, 18, and 30 mo of age were examined. Na+-K+-ATPase activity, measured by K+-stimulated 3- O-methylfluorescein phosphatase activity, increased by ∼50% in a mixed Gast homogenate from 30-mo-old compared with 6- and 18-mo-old rats. Advancing age was associated with markedly increased α1- and β1-subunit, and decreased α2- and β2-subunit in red and white Gast. In soleus, there were similar changes in expression of α1- and α2-subunits, but levels of β1-subunit were unchanged. Functional Na+-K+-ATPase units, measured by [3H]ouabain binding, undergo muscle-type specific changes. In red Gast, high-affinity ouabain-binding sites, which are a measure of α2-isozyme, increased in 30-mo-old rats despite decreased levels of α2-subunit. In white Gast, by contrast, decreased levels of α2-subunit were accompanied by decreased high-affinity ouabain-binding sites. Finally, patterns of expression of the four myosin heavy chain (MHC) isoforms (type I, IIA, IIX, and IIB) in these muscles were similar in the three age groups examined. We conclude that, in the skeletal muscles of F-344/BN rats, advancing age is associated with muscle type-specific alterations in Na+-K+-ATPase activity and patterns of expression of α- and β-subunit isoforms. These changes apparently occurred without obvious shift in muscle fiber types, since expression of MHC isoforms remained unchanged. Some of the alterations occurred between middle-age (18 mo) and senescence (30 mo), and, therefore, may be attributed to aging of skeletal muscle.

scholarly journals Maximal oxygen uptake is proportional to muscle fiber oxidative capacity, from chronic heart failure patients to professional cyclists

2016 ◽  
Vol 121 (3) ◽  
pp. 636-645 ◽  
Author(s):  
Stephan van der Zwaard ◽  
C. Jo de Ruiter ◽  
Dionne A. Noordhof ◽  
Renske Sterrenburg ◽  
Frank W. Bloemers ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Chronic Heart Failure ◽  
Oxygen Uptake ◽  
Maximal Oxygen Uptake ◽  
Ex Vivo ◽  
Vastus Lateralis ◽  
Oxidative Capacity ◽  
Heart Failure Patients ◽  
Mitochondrial Oxidative Capacity

V̇o2 max during whole body exercise is presumably constrained by oxygen delivery to mitochondria rather than by mitochondria's ability to consume oxygen. Humans and animals have been reported to exploit only 60-80% of their mitochondrial oxidative capacity at maximal oxygen uptake (V̇o2 max). However, ex vivo quantification of mitochondrial overcapacity is complicated by isolation or permeabilization procedures. An alternative method for estimating mitochondrial oxidative capacity is via enzyme histochemical quantification of succinate dehydrogenase (SDH) activity. We determined to what extent V̇o2 max attained during cycling exercise differs from mitochondrial oxidative capacity predicted from SDH activity of vastus lateralis muscle in chronic heart failure patients, healthy controls, and cyclists. V̇o2 max was assessed in 20 healthy subjects and 28 cyclists, and SDH activity was determined from biopsy cryosections of vastus lateralis using quantitative histochemistry. Similar data from our laboratory of 14 chronic heart failure patients and 6 controls were included. Mitochondrial oxidative capacity was predicted from SDH activity using estimated skeletal muscle mass and the relationship between ex vivo fiber V̇o2 max and SDH activity of isolated single muscle fibers and myocardial trabecula under hyperoxic conditions. Mitochondrial oxidative capacity predicted from SDH activity was related ( r2 = 0.89, P < 0.001) to V̇o2 max measured during cycling in subjects with V̇o2 max ranging from 9.8 to 79.0 ml·kg−1·min−1. V̇o2 max measured during cycling was on average 90 ± 14% of mitochondrial oxidative capacity. We conclude that human V̇o2 max is related to mitochondrial oxidative capacity predicted from skeletal muscle SDH activity. Mitochondrial oxidative capacity is likely marginally limited by oxygen supply to mitochondria.

Effects of chronic heart failure on skeletal muscle vascular transport capacity of rats

1993 ◽  
Vol 264 (3) ◽  
pp. H686-H691 ◽  
Author(s):  
Richard M. McAllister ◽  
M. Harold Laughlin ◽  
Timothy I. Musch
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Chronic Heart Failure ◽  
Left Ventricular ◽  
Transport Capacity ◽  
Vascular Transport ◽  
Lv Dysfunction ◽  
Regional Flow ◽  
Wide Range ◽  
Capillary Pressures

The purpose of this study was to determine the effects of chronic heart failure (HF) on the vascular transport capacity of rat skeletal muscle. A large myocardial infarction (MI) was surgically produced in rats by ligating the left main coronary artery (n = 10). Sham operations were performed in control animals (Sham, n = 4). The vascular transport capacity of each animal's hindquarters was determined 8–9 mo post-MI to ensure that each rat was in a chronic state of left ventricular (LV) dysfunction and HF. With the use of an isolated, maximally vasodilated hindquarters preparation, we found that perfusion pressures, capillary pressures, capillary filtration coefficients, and precapillary vascular resistances were similar for the two groups under isogravimetric conditions. In contrast, postcapillary resistance was elevated (Sham, 0.9 ± 0.2; MI, 1.5 ± 0.2 mmHg·m−1·min·100 g; P = 0.03), and flow to the hindquarters was reduced for rats in chronic HF compared with controls (Sham, 16.1 ± 2.3; MI, 12.1 ± 0.9 ml·min−1·100 g−1; ,P = 0.07). Vascular flow capacity (VFC) for the hindquarters was similar for control rats and rats with chronic HF across a wide range of perfusion pressures (20–60 mmHg). However, regional flow capacities were reduced in soleus and red gastrocnemius but not in white gastrocnemius muscles of rats in chronic HF compared with controls. These results suggest that the VFC of muscle comprised primarily of high oxidative fibers is selectively reduced in rats with chronic HF. Given the obligatory role for high oxidative muscle fibers in locomotion, these decrements in VFC may contribute to the decreased exercise tolerance commonly found with this disease. blood flow; vascular resistance; radiolabeled microspheres Submitted on May 8, 1992 Accepted on October 16, 1992

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