Limited exercise capacity is a hallmark symptom of patients with chronic heart failure (CHF), originally thought to result from reduced skeletal muscle blood flow due to impaired cardiac pumping capacity (36). However, this is unlikely to be the only mechanism involved because improvement of cardiac performance is not paralleled by the increase in exercise tolerance (44). Exercise capacity is also poorly correlated with ejection fraction (EF) (10), and reduced muscle performance is evident even when exercising smaller muscle groups in which bulk blood flow is not limited by reduced cardiac output (4).
Alternative explanations for the skeletal muscle dysfunction have been proposed during the last decades. Altered changes in metabolites such as accumulation of lactate and decreased oxidative capacity may both contribute to the reduced exercise capacity in heart failure. Recently, Okada et al. (27) suggested that alterations in myosin content could explain skeletal muscle strength deficit in CHF patients. Also, the role of Ca2+ handling as a factor in the CHF-associated skeletal muscle dysfunction has been investigated. It has been reported that CHF rats have increased levels of sarcoplasmic Ca2+ ATPase (SERCA) and ryanodine receptor (RyR) in the soleus muscle (19), although a reduction in SERCA is also reported (30). The results regarding the Ca2+ transient during fatigue are also inconclusive because both maintained (20) and reduced transients have been reported (29) in the skeletal muscle of CHF rats. Although experimental studies seem to be inconclusive, they point to significant alterations of intracellular Ca2+ handling in the skeletal muscle in CHF. Some researchers even argue that reduced Ca2+ release is the major determinant of skeletal muscle fatigue (43). Whether altered Ca2+ handling is also part of the multifactorial skeletal muscle dysfunction in CHF has not been tested in humans.
Before the early 1980s, patients with heart failure were advised to live sedentary lives. Today, it seems clear that exercise reduces both hospitalization and mortality and increases quality of life for these patients (26). Even high-intensity exercise seems to be well tolerated (45), and physical inactivity can accelerate the disease progression (17). Training by running or cycling taxing cardiac output consistently leads to higher V˙O2max and improves exercise tolerance in CHF patients (11), but also local muscle training has beneficial effects, such as increasing peak workload, endurance, and oxidative capacity, contributing to improved skeletal muscle function (12).
By performing endurance training only with the quadriceps femoris (QF) muscle of one leg (approximately 2 kg), healthy subjects as well as CHF patients can tolerate much higher workloads per kilogram of muscle for rather long exercise times compared with whole-body exercise such as bicycling (21). This ensures a high demand on the exercising muscles, including the contractile apparatus, the energy metabolism, and the Ca2+ handling proteins, despite limited pumping capacity of the failing heart. Thus, the effects of training can be evaluated independently of heart function. Such training has been investigated in a limited number of studies, none of which have included a healthy control (HC) group for other purposes than baseline characteristics. Training effects on CHF patients thus cannot be distinguished from those of the healthy, age-matched population. In the present study, we include a training HC group and investigate two main hypotheses. First, at baseline, we expect that skeletal muscle sarcoplasmic reticulum (SR) Ca2+ handling will be different in the muscle from CHF patients compared with that from HC. Second, we also expect that SR function may not be improved by training to the same extent in CHF as in HC by exercising the QF muscle of one leg.
Eleven sedentary patients with stable CHF, New York Heart Association (NYHA) classes I and II, caused by ischemia were recruited from Oslo University Hospital, Ullevål. Subjects with other heart failure causes were not included in the study. EF was below 35%, measured not longer than 3 months before inclusion. Thirteen HC were included as controls. To further minimize confounding factors, we chose to include only male subjects because previous studies have reported differences in skeletal muscle properties in men and women with CHF (9). Refer to Supplemental Digital Content (SDC) for additional inclusion and exclusion criteria (SDC5 Table 1: Inclusion and exclusion criteria, http://links.lww.com/MSS/A18). At inclusion, all subjects underwent a series of tests: knee extensor peak torque, spirometry, ergometer cycle test, biopsies from vastus lateralis bilaterally, and computed tomographic (CT) examination of both thighs. After the training period, the CT examination and the biopsy procedure were repeated. Also, peak torque was retested along with evaluation of peak power. All CHF patients used β-blockers and either angiotensin conversion enzyme inhibitors (ACEi) or angiotensin II (ATII) receptor blockers (Table 1). Medical treatment in the CHF patients was continued throughout the study period because cessation would have been considered ethically unacceptable. Written informed consent was obtained from all the subjects included. The investigation conforms to the principles outlined in the Declaration of Helsinki and was approved by the regional ethics committee.
Spirometry, V˙O2peak test, and work ECG.
With patients on an ergometer bicycle (Schiller ERG911, Baar, Switzerland), V˙O2 was measured every 20 s (Vmax 229; SensorMedics, Yorba Linda, CA) during stepwise increments of intensity (10 W·min−1) until exhaustion to determine V˙O2peak. The CHF patients started at 50 W, whereas the HC started at 100 W. For the test to be valid, a Borg score ≥ 18 and RER > 1.0 at exhaustion were required. ECG were obtained from all the test persons during cycling.
CT scanning was performed on a HiSpeed or a LightSpeed scanner (General Electric, Paris, France). The examination was a helical scan from spina iliaca anterior inferior through patella on both thighs. Five-millimeter slices were reconstructed every 5 mm. Quadriceps volume was calculated using an Advantage Workstation (General Electric), and cross-sectional area (CSA) was measured in the middle of the thigh by a personnel blinded for patient group and training status. The interobserver correlation between the two technicians measuring CSA and outlining the muscle for volume analysis was very good (r 2 > 0.99).
Skeletal muscle biopsy.
Percutaneous needle biopsy of the vastus lateralis was performed under sterile conditions with local anesthesia (Xylocaine adrenaline, 10 mg·mL−1 + 5 μg·mL−1; AstraZeneca, Oslo, Norway), using a 6-mm Pelomi needle (Albertslund, Denmark) with manual suction. Samples for preparation of SR vesicles for measurements of Ca2+ uptake and release were homogenized (Polytron 1200 homogenizer; Kimemtica AG, Luzern, Switzerland) on ice in a Tris-sucrose buffer (pH 7.9) supplied with a phosphatase inhibitor (P2850; Sigma-Aldrich, Oslo, Norway). The rest of the biopsies were frozen in isopentane on dry ice and stored at −80°C for other analyses.
Ca2+ uptake, release, and leak.
SR function was analyzed in an LS50B fluorometer (Perkin Elmer, Oslo, Norway) at 37°C by the use of indo-1. K d indo-1 at 37°C is 0.13 μM (38). Calcium pumping in the SR vesicles was initiated by the addition of 1.1 mM of Mg-ATP and blocked by 1.5 μM of thapsigargin (SDC1 Figure 1: Indo-1 emission ratio, http://links.lww.com/MSS/A14). SR leak was evaluated during the next 60 s and reported as the linear rate of rise in arbitrary units (au·s−1). Calcium release was initiated by 11 mM adding of 4-chloro-m-cresol. The fluorescence ratio was converted to [Ca2+] by the following equation: [Ca2+] = (R − R min)/(R max − R)K d indo-1(S f 2/S b 2), where S f 2/S b 2 = 2.7. R min and R max were determined by reading the indo-1 ratio after applying 3.3 mM of EGTA and 4.8 mM of CaCl2, respectively.
Enzyme activity was determined in homogenized vastus lateralis biopsies according to an established spectrophotometric assay (34). 5,5′-Dithiobis-(2-nitrobenzoic acid) was added, and the free mercaptide ion was measured at 412 nm.
Western blot was performed on total homogenate. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) (4%-15% for RyR, 7.5% for SERCA1, and 15% for phospholamban) was performed before blotting and probing with primary antibodies (SERCA1: MA3-912, SERCA2: MA3-919 (both Affinity Bioreagents, Golden, CO); total PLB: A010-14, Ser16 P-PLB: A010-12, Thr17 P-PLB: A010-13 (all Badrilla, Leeds, UK)). Immunoreactivity was detected by the enhanced chemiluminescence method (Amersham, Piscataway, NJ) with a Fujifilm camera (LAS-1000 or 4000; Fujifilm, Stockholm, Sweden). Myofibrillar proteins were separated by glycerol-SDS-PAGE. Identical amounts of protein were applied in each well. Gels were stained sequentially by Pro Q Diamond and SYPRO Ruby (both M33305; Invitrogen, Oslo, Norway) for phosphorylated and total proteins, respectively. The fluorescence was detected by Typhoon laser scanner (9410; GE Healthcare, Oslo, Norway) and quantified by Imagequant (GE Healthcare). Amounts of protein after the training period were normalized to the protein content in biopsies from that individual muscle before training.
Training protocol, peak torque, and peak power.
One-legged dynamic knee extensor training was performed on a knee extension ergometer, modified by Hallén et al. (14). This setup restricts exercise to the quadriceps muscle unilaterally. The other leg was hanging loosely from the chair and did not move during exercise. This leg served as the control. The limited muscle mass engaged will not challenge cardiac output, ensuring sufficient oxygen supply to the working muscle despite the reduced cardiac output of CHF patients (21). The patients were randomly assigned to exercise the dominant or the nondominant leg. Two low-intensity (LI), one moderate-intensity (MI), and one high-intensity (HI) exercise sessions were performed weekly for 6 wk with the same relative workload for the two groups. HI was defined as the workload that exhausted the test subject after 20 min of exercise. LI (∼70% of HI) consisted of 60 min of exercise, whereas MI (∼80% of HI) consisted of 20 min of warm-up at LI followed by 40 min of exercise at MI. HI exercise consisted of 20 min of exercise at HI with 10 min of warm-up and 10 min of cool-down, both at LI. All exercises were performed at 60 rounds per minute. During a separate exercise session at HI, a catheter was placed in the femoral vein on the trained leg under local anesthesia (10 mg·mL−1 Xylocaine; AstraZeneca). Blood was sampled and analyzed for lactate (YSI 1500 Sport, Yellow Springs, OH).
Maximum voluntary isokinetic strength (peak torque) was tested on an isokinetic dynamometer (REV9000; Technogym, Gambettola, Italy). The range of motion was set to a knee angle from 20° to 90° and the angle speed to 60°·s−1. Warm-up was done on an ordinary cycle ergometer (50 W for 10 min).
Peak power was tested on the knee extension ergometer using a stepwise incremental (2 W·min−1) protocol. The tests were performed on one leg at a time on two consecutive days after the training protocol. Start load was individually adjusted to cause exhaustion between 4 and 10 min after the start of testing. A physician was always present during testing of CHF patients.
Data are presented as mean ± SEM. SEM is also indicated on the figures. P < 0.05 was considered statistically significant. Protein measurements and Ca2+ handling properties after the training period were related (either as ratios or as Δ values) directly to the corresponding pretraining value. The post/pre ratios were log transformed to approximate the data to normal distribution. Differences between groups were tested by Student's t-test. All statistical analyses were performed on either Statistica (StatSoft, Inc. (2007), Tulsa, OK) or Microsoft Excel 2007.
CHF patients had 39% lower V˙O2peak compared with HC, and a low EF confirmed the heart failure diagnosis (Table 2). There were no incidences of angina-suspected chest pain or ischemia-suspected ECG alterations during the test period. At a one-leg HI workload, the femoral venous lactate level was not different between the groups (6.8 ± 0.4 mmol·L−1 for CHF vs 6.2 ± 0.5 mmol·L−1 for HC). Furthermore, the duration of each training session was the same for the two groups.
Baseline characteristics are summarized in Figure 1. There were no differences between the left and the right legs for any of the parameters. Thus, averaged values are presented. At inclusion, CHF patients were 17% weaker than HC as measured by peak torque (Fig. 1A), but if normalized to either quadriceps volume or CSA (Fig. 1B), the statistical differences between the groups disappeared. Peak power was 29% lower in the untrained leg of CHF patients compared with HC (P < 0.001). This difference persisted even when correcting for CSA and is indicative of a reduced skeletal muscle function in CHF. Citrate synthase (CS) activity was not significantly different (Fig. 1C). Also, there was no significant difference in myosin heavy chain (MHC) distribution. Each of the three fiber types constituted about one-third of the total number of fibers in both groups (Fig. 1D). The level of SERCA2 was 51% higher in CHF compared with HC, and the PLB monomer/pentamer ratio was 41% lower in the CHF group compared with HC (Table 3). There were no significant differences between CHF and HC regarding SR Ca2+ uptake and release rate (Figs. 1E and F). However, SR Ca2+ leak was 24% lower in CHF patients compared with HC (Fig. 1G).
Six weeks of endurance training did not increase peak torque in trained leg (Fig. 2A) despite increased quadriceps CSA (by 9% and 7% for HC and CHF) and volume (by 6% and 9% for HC and CHF; Fig. 2B). For the HC group, training also increased both volume and CSA in the untrained leg significantly, by 7% and 8%, respectively. However, after the training period, peak power was higher in the trained leg compared with the untrained leg by 10% and 14% for HC and CHF, respectively (Fig. 2C). Compared with the baseline levels, CS activity in the trained leg increased by 34% ± 9% in HC and 27% ± 9% in CHF patients (Fig. 2D). There was no increase in CS activity in the untrained leg of either group. MHC distribution was not significantly changed in either group (SDC5 Table 2: MHC fiber-type distribution, http://links.lww.com/MSS/A18).
For the HC, training increased the Ca2+ release rate (from 0.029 ± 0.003 to 0.043 ± 0.002 μM·s−1) and reduced the leak (from 15.5 ± 1.3 to 10.9 ± 2.4 au·s−1) of Ca2+ from SR in the trained leg (Figs. 3B and C). Also, in the untrained leg, the release rate was higher after the training period (increased from 0.029 ± 0.003 to 0.049 ± 0.003 μM·s−1; Fig. 3B). In relation to this, the RyR amount tended to be elevated (P = 0.053), and the RyR phosphorylation level was nominally reduced in the trained leg (Fig. 4A) of the HC group. For the CHF patients, there was no significant effect of training on SR Ca2+ release rate or leak, and the RyR amount decreased by 18% in the trained leg. For this group, however, the Ca2+ uptake rate in the untrained leg was significantly higher after the training period (from 0.008 ± 0.001 to 0.014 ± 0.003 μM·s−1; Fig. 3A). There was no change in SERCA amount or isoform in any of the groups, and there were no alterations in PLB that could explain the effects of training. However, the training-induced alteration in PLB was different for the two groups (Figs. 4A and B). Ser16 phosphorylation was up-regulated in the trained leg in HC (Fig. 4A) but was lower in the untrained leg of the CHF group (Fig. 4B). Both for the total RyR amount and the phosphorylated form, the two groups showed different effects of training. Total RyR was reduced, but phosphorylation was increased in CHF compared with HC. See SDC for representative Western blots (SDC2-4 for representative Western blots (SDC Figures 2-4: SDS-PAGE gels, http://links.lww.com/MSS/A15, http://links.lww.com/MSS/A16, http://links.lww.com/MSS/A17).
The main finding of this study is that only by a lower Ca2+ leak from SR is Ca2+ handling in the skeletal muscle of CHF patients different from that of HC. Peak power was lower in patients compared with HC, even when correcting for CSA. Training of QF resulted in increased CS activity and improved peak power in the trained leg in both groups without alterations in MHC distribution. Ca2+ release rate was higher and Ca2+ leak was reduced in the trained leg for HC. As hypothesized, in the CHF group, training had no significant effects on calcium handling.
There were no significant differences in peak torque between HC and CHF patients when correcting for CSA. This is consistent with several previous studies (24), although some also report that reduced skeletal muscle strength cannot solely be accounted for by a reduction in muscle mass (39). The lack of agreement in the literature could arise from differences in severity and treatment of heart failure or be due to the different techniques used to measure muscle mass or strength. Concurrent with previous reports, we found a functional deficit in the skeletal muscle of patients with heart failure with a lower peak power in the untrained leg of CHF patients compared with HC.
Several investigators have reported that skeletal muscle of CHF patients is characterized by an isoform switch toward a less fatigue-resistant fiber type (35). This switch could be unrelated to deconditioning (8). However, this finding is not confirmed in the present study. One explanation for this could be that the patients enrolled might have milder degrees of heart failure and, consequently, only minor alteration of the muscle phenotype. However, the patients in the present study have about the same EF and NYHA class as patients in other studies that evaluate skeletal muscle alterations in CHF (40). An alternative explanation for the lack of isoform switch could be the medication of the patient with heart failure. During the last decades, heart failure is treated more intensely and with drugs such as ACEi. Several investigators have reported that this drug seems to also have effects on the skeletal muscle in heart failure. ACEi could induce a switch from type II to type I fibers (40) and protect mitochondrial function (46). Another drug group, the ATII receptor blockers, has similar effects (6). However, there are also contradictory reports that fail to demonstrate the effects of ACEi in the skeletal muscle of CHF patients (32). All CHF patients in the present study used either ACEi or ATII receptor blockers. Thus, we cannot exclude that usage of these drugs could explain why CHF patients had the same MHC isoform distribution as HC.
Other drugs used by the CHF patients in the present study (Table 1) probably do not affect MHC isoform. High doses of furosemide have been reported to decrease the level of potassium in the rat skeletal muscle (3), and statins could have negative effects on skeletal muscle mitochondrial ATP-producing capacity (18). The usage of statins is, however, associated with skeletal muscle complaints, and although the underlying mechanisms remain unclear, it is hypothesized that increased Ca2+ leak could contribute to the muscle ache (33). In the present study, there is no relation between the usage of statins and the increased rate of Ca2+ leak.
Training effects in HC.
Effects of training were readily identified as increased peak power and CS activity in the trained leg. Hypertrophy was evident in both trained and untrained legs after training, but no change in muscle strength or MHC distribution was demonstrated.
After the training period, the release rate of Ca2+ increased bilaterally, and in the trained leg, Ca2+ leak was reduced (Fig. 3). This contrasts with "leaky" and dyssynchronous RyR that are identified after an acute bout of exercise (2). Increased release rate and reduced leak corresponded to the nominal rise in RyR amount and reduced RyR phosphorylation. It has been shown that dephosphorylation of RyR leads to binding of calstabin 1 (23), reducing leak and increasing release rate of Ca2+ from SR. The reduced leak and increased release rate could be related to the higher levels of Ca2+ in the SR after training compared with those before training. This could, in turn, result in an improvement of muscle function.
A similar training regimen as in the present study using young healthy subjects resulted in a switch toward a slow fiber-type isoform, with depressed SERCA1 and reduced SR uptake rate of Ca2+ (13). Our data do not support these findings, which could be due to an age effect. Judging from the relatively large increase in Ser16 PLB in the trained leg, the unaltered Ca2+ uptake kinetics was unexpected because phosphorylation of PLB on either Ser16 or Thr17 is thought to relieve the PLB-induced inhibition of SERCA (41). In the present study, relative SERCA abundance was also unaltered. However, the fact that skeletal muscle training responses seem to be age dependent is not surprising. Although there is good evidence that training increases muscle mass and strength also in the elderly (25), muscle plasticity may decrease with age (7), and training-induced activation of the mTOR pathway is attenuated (28) with a lower differentiation of satellite cells (5). The satellite cell pool is also reduced with aging (16). Further, 6 wk of endurance training is possibly not enough time to allow for the MHC isoform switch to occur. However, endurance training programs lasting as long as 6 months have also failed to show any significant changes in MHC isoform in the elderly (15).
In summary, in HC, local exercise gives rise to alterations in calcium handling mostly affecting RyR and Ca2+ leak and release.
Training effects in CHF patients.
One-leg exercise could be maintained at HI for 20 min with about the same lactate concentration in the femoral venous blood as in HC. Thus, anaerobic metabolism in the exercising muscle was not more prominent in CHF, indicating that the CHF condition did not compromise muscle perfusion when only one quadriceps femoris muscle was active. Training effects were apparent as increased peak power, elevated CS activity, and increased volume and CSA in trained leg (Figs. 2B-D). There were no alterations in MHC fiber-type distribution.
The heart failure condition is characterized by a hyperadrenergic state, and in heart failure animal models, RyR1 is hyperphosphorylated, depleted of calstabin 1, and leaky (31,37). This is associated with increased frequency and decreased amplitude of Ca2+ sparks (42). However, little is known about the phosphorylation status of RyR in the skeletal muscle from CHF patients. Because all CHF patients in the present study used β-adrenoceptor blockers as part of their standard medication (Table 1), it is possible that RyR phosphorylation status is normal or even reduced in these patients. Further, the β-adrenergic receptors are probably down-regulated or less sensitive in patients with heart failure (22). Accordingly, the altered adrenergic drive due to training could be blunted. We failed to find any regulation in the degree of RyR phosphorylation in the CHF group. Instead, we found a down-regulation of the channel itself but with no changes of Ca2+ release or leak. Because CHF patients had a lower SR Ca2+ leak at baseline and that exercise did not alter the leak in this group although it did in the HC group, it is tempting to speculate that whatever positive effect training had on leak, this effect seemed to be already attained in the CHF group, maybe because of medication. It seems at least that the observed training effect can be attained without any effect on intracellular Ca2+ cycling. Further studies including training of patients with atherosclerosis that use fewer drugs than patients with heart failure are needed to elucidate this issue.
Systemic effects of local muscle training?
It was unexpected that local muscle training decreased SR Ca2+ leak and increased both quadriceps CSA and volume in the untrained leg for HC. It is also surprising that these effects were absent in the CHF group. The most obvious explanation for the alterations in untrained leg in HC is that participation in the study led to a higher awareness regarding the beneficial effects of training resulting in an increase in physical activity. However, the participants were specifically instructed to maintain physically inactive throughout the study, and when specifically asked, none in either group reported to have increased their daily activity level. Also, an increase in physical activity should affect the HC and CHF group equally. Another possible explanation for the changes in untrained leg is that local training could trigger the production of humoral factors in the skeletal muscle that in turn might have beneficial effects also in the resting control muscle. Local training influences the level of cytokines in the muscle and in plasma (1), but whether these cytokines have effects also in resting muscle tissue throughout the body is a captivating idea that should be pursued further. Lastly, the effects in resting leg would be relatively smaller if the training effects were more pronounced. Therefore, it could be argued that the training intensity in the present study is set to low and that the intensity should be higher for future studies.
This study is the first to investigate skeletal muscle Ca2+ handling in the muscle of patients with heart failure. In addition, it is the first study on local skeletal muscle function and trainability that includes an HC group that undergoes the same training protocol as the heart failure patients. In conclusion, CHF patients had similar effects of local muscle training as HC, but for CHF patients, this effect was unrelated to altered calcium handling. For HC training, effects were associated with changes in RyR function, and some of the changes could be systemic in nature. Local skeletal muscle function in CHF patients compared with HC was unexpectedly normal compared with what has previously been reported in experimental studies. We speculate that medication, such as β-blockers and maybe also ACEi/ ATII receptor blockers, to some extent reverses the dysfunction and explains why findings from experimental studies are not reproduced here.
Clinical Trial Registration: http://www.clinicaltrial.gov/ (Identifier: NCT00156234).
This work was supported by the Norwegian Foundation for Health and Rehabilitation, the University of Oslo, the Oslo University Hospital, the Anders Jahre's Fund for the Promotion of Science, the South-Eastern Norway Regional Health Authority, and the Norwegian School of Sport Sciences, Oslo, Norway. Conflict of interest: None declared.
The valuable contributions from Martin Sökjer, Mona Risdal, and Lena Korsmo (Department of Cardiovascular Radiology, Oslo University Hospital), Ståle Nygård (Institute for Experimental Medical Research and Bioinformatic Core Facility, Oslo University Hospital), Elisabeth Edvardsen (Department of Pulmonary Medicine, Laboratory of Respiratory Physiology, Oslo University Hospital), Svein Lerstein, Bernt Sivert Nymark, Sjur Ole Svarstad, Annete Hilde, and Ingrid Ugelstad (Department of Physical Performance, NSSS) are greatly acknowledged.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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