Effects of high-intensity training on prostate cancer-induced cardiac atrophy.

BACKGROUND: Recent evidence suggests prostate cancer independent of treatment has atrophic effects on whole heart and left ventricular (LV) masses, associated with reduced endurance exercise capacity. In a pre-clinical model, we tested the hypothesis that high-intensity training could prevent cardiac atrophy with prostate cancer and alter cardiac protein degradation mechanisms. METHODS: Dunning R-3327 AT-1 prostate cancer cells (1×105) were injected into the ventral prostate lobe of 5-6 mo immunocompetent Copenhagen rats (n=24). These animals were randomized into two groups, tumor-bearing exercise (TBEX, n=15) or tumor bearing sedentary (TBS, n=9). Five days after surgery, TBEX animals began exercise on a treadmill (25 m/min, 15° incline) for 45-60 min/day for 18±2 days. Pre-surgery (Pre), and post-exercise training (Post) echocardiographic evaluation (Vivid S6, GE Health Care), using the parasternal short axis view, was used to examine ventricle dimensions. Markers of protein degradation (muscle atrophy F-box, Cathepsin B, Cathepsin L) in the left ventricle were semi-quantified via Western Blot. RESULTS: There were no significant differences in tumor mass between groups (TBEX 3.4±0.7, TBS 2.8±0.6 g, P=0.3), or body mass (TBEX 317±5, TBS 333±7 g, P=0.2). Heart-to-body mass ratio was lower in TBS group compared to TBEX (2.3±0.1 vs. 2.5±0.1 mg/g, P<0.05). LV/body mass ratio was also lower in the TBS group (1.6±0.1 vs. 1.8±0.1 mg/g, P<0.05). From Pre-Post, TBEX had significant increases in SV (~20% P<0.05) whereas TBS had no significant change. There were no significant differences between groups for markers of protein degradation. CONCLUSION: This study suggests that high-intensity exercise can improve LV function and increase LV mass concurrent with prostate cancer development, versus sedentary counterparts. Given cardiac dysfunction often manifests with conventional anti-cancer treatments, a short-term high-intensity training program, prior to treatment, may improve cardiac function and fatigue resistance in cancer patients.

Effects of prostate cancer and exercise training on left ventricular function and cardiac and skeletal muscle mass.

Prostate cancer was found to reduce cardiac and left ventricle (LV) masses in association with diminished exercise capacity in rats. We tested the hypothesis that exercise training will mitigate prostate cancer-induced cardiac and skeletal muscle atrophy and improve LV function versus sedentary tumor-bearing counterparts. Copenhagen rats ( n = 39; ~5 mo old) were randomized into four groups: exercise-trained tumor-bearing (EXTB) or control (EXCON) and sedentary tumor-bearing (SEDTB) or control (SEDCON). Dunning R-3327 prostate cancer cells were injected orthotopically in 19 of the 39 animals. Treadmill exercise training was performed for 60 min/day for ~30 days. Animals underwent echocardiography to examine ventricle dimensions "Pre-" cancer injection or exercise (PRE) and 15 (Post 1) and 32-35 (Post 2) days after cancer cell injection with tissues collected after Post 2. LV TNF-α and IL-6 concentrations were measured post mortem. Cardiac and LV mass of SEDTB animals were lower than all groups ( P < 0.05). Tumor mass was negatively correlated with LV mass in EXTB (-0.75, P < 0.02) and SEDTB animals (-0.72, P < 0.02). EXCON group had higher stroke volume Post 2 assessment compared with both sedentary groups ( P < 0.05) but not EXTB animals. No difference in LV [IL-6] or [TNF-α] was found between the cancer groups. The current investigation demonstrates prostate cancer, independent of anticancer treatment, significantly reduces cardiac mass and LV mass as well as locomotor muscle masses. However, moderate-intensity exercise training can mitigate cardiac and skeletal muscle atrophy with prostate cancer and preserve the cardiac phenotype (i.e., mass and function) to that of the healthy sedentary group. NEW & NOTEWORTHY This study demonstrates the atrophic effects of prostate cancer on cardiac and skeletal muscle mass independent of anticancer treatment(s) that can be mitigated with moderate-intensity exercise. These findings have important implications for potentially improving the quality of life as well as therapeutic outcomes for patients with prostate cancer.

Vascular and autonomic changes in adult cancer patients receiving anticancer chemotherapy.

Chemotherapy is associated with acute and long-term cardiotoxicity. To date, risk assessment has primarily focused on the heart; however, recent findings suggest that vascular and autonomic function may also be compromised. Whether this occurs during chemotherapy treatment remains unknown. Therefore, the present study evaluated carotid artery stiffness, cardiovagal baroreflex sensitivity (cBRS), and heart rate variability (HRV) in cancer patients currently being treated with adjuvant chemotherapy. Eleven current cancer patients receiving adjuvant chemotherapy and 11 matched (1:1) controls were studied. Carotid artery stiffness was assessed via two-dimensional ultrasonography. cBRS was assessed from the spontaneous changes in beat-to-beat time series of R-R interval and systolic blood pressure via the cross-correlation technique. HRV was assessed using the standard deviation of R-R intervals (SDNN) and low (LF) and high (HF) power frequencies. Carotid artery ß-stiffness was significantly higher in the cancer patients compared with control participants (8.0 ± 0.8 vs. 6.3 ± 0.6 U, respectively; P = 0.02). cBRS was lower in the cancer patients compared with controls (4.3 ± 0.7 vs. 10.7 ± 1.9 ms/mmHg, respectively; P = 0.01), and all indices of HRV were lower in the cancer patients (SDNN, P = 0.02; LF, P = 0.01; HF, P = 0.02). There was no significant correlation between ß-stiffness and cBRS ( P = 0.4). However, LF power was significantly correlated with cBRS (r = 0.66, P < 0.001). Compared with matched healthy controls, cancer patients undergoing chemotherapy demonstrated a significantly higher arterial stiffness and lower cBRS. The previously reported adverse effects of chemotherapy on the heart appear to also influence other aspects of cardiovascular health. NEW & NOTEWORTHY Patients treated with anticancer chemotherapy exhibit an impaired baroreflex control of arterial blood pressure and increased arterial stiffness. These findings hold significant value, in particular as part of a risk-stratification strategy in current cancer patients receiving chemotherapy. This is the first investigation, to our knowledge, to demonstrate an attenuated spontaneous baroreflex control of arterial blood pressure in cancer patients currently undergoing chemotherapy.

Prostate cancer reduces endurance exercise capacity in association with reductions in cardiac and skeletal muscle mass in the rat.

Exercise capacity is reduced in prostate cancer patients concurrently treated with androgen deprivation therapy compared to healthy counterparts. We tested the hypothesis that prostate cancer independently reduces endurance exercise capacity in a preclinical orthotopic prostate tumor model. Male Copenhagen rats performed an initial treadmill running test to exhaustion. The rats' prostates were subsequently injected with either prostate tumor cells (R-3327 AT-1, tumor bearing, n=9) or vehicle control (sham, n=9) and the treadmill tests were repeated four and eight weeks post-surgery. Left ventricle contractility (LV Δpressure/Δtime) was subsequently measured under anesthesia and the heart and select hindlimb muscles were dissected and weighed. Initial times to exhaustion were not different between groups (sham: 28.24±1.26, tumor bearing: 28.63±2.49 min, P=0.90). Time to exhaustion eight weeks post-surgery was reduced compared to initial values for both groups but was significantly lower in the tumor bearing (13.25±1.44 min) versus the sham (21.17±1.87 min, P<0.01) group. Within the tumor bearing group, LV Δpressure/Δtime was significantly negatively correlated with tumor mass (-0.71, P<0.05). Body mass at eight weeks post-surgery was not different between groups (P=0.26) but LV mass (↓17%, P<0.01), as well as the mass of select hindlimb skeletal muscles, was significantly lower in the tumor bearing versus sham group. Within the tumor bearing group, LV muscle mass was significantly negatively correlated with prostate tumor mass (r=-0.85, P<0.01). Prostate cancer reduced endurance exercise capacity in the rat and reductions in cardiac function and mass and skeletal muscle mass may have played an important role in this impairment.

The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in rats with ligated femoral arteries.

Mechanical and metabolic stimuli arising from contracting muscles evoke the exercise pressor reflex. This reflex is greater in a rat model of simulated peripheral arterial disease in which a femoral artery is chronically ligated than it is in rats with freely perfused femoral arteries. The role played by the mechanically sensitive component of the exaggerated exercise pressor reflex in ligated rats is unknown. We tested the hypothesis that the mechano-gated channel inhibitor GsMTx4, a relatively selective inhibitor of mechano-gated Piezo channels, reduces the exercise pressor reflex in decerebrate rats with ligated femoral arteries. Injection of 10 µg of GsMTx4 into the arterial supply of the hindlimb reduced the pressor response to Achilles tendon stretch (a purely mechanical stimulus) but had no effect on the pressor responses to intra-arterial injection of α,ß-methylene ATP or lactic acid (purely metabolic stimuli). Moreover, injection of 10 µg of GsMTx4 into the arterial supply of the hindlimb reduced both the integrated pressor area (control 535 ± 21, GsMTx4 218 ± 24 mmHg·s; P < 0.01), peak pressor (control 29 ± 2, GsMTx4 14 ± 3 mmHg; P < 0.01), and renal sympathetic nerve responses to electrically induced intermittent hindlimb muscle contraction (a mixed mechanical and metabolic stimulus). The reduction of the integrated pressor area during contraction caused by GsMTx4 was greater in rats with ligated femoral arteries than it was in rats with freely perfused femoral arteries. We conclude that the mechanically sensitive component of the reflex contributes to the exaggerated exercise pressor reflex during intermittent hindlimb muscle contractions in rats with ligated femoral arteries.

The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats.

KEY POINTS: Mechanical and metabolic stimuli from contracting muscles evoke reflex increases in blood pressure, heart rate and sympathetic nerve activity. Little is known, however, about the nature of the mechano-gated channels on the thin fibre muscle afferents that contribute to evoke this reflex, termed the exercise pressor reflex. We determined the effect of GsMTx4, an inhibitor of mechano-gated Piezo channels, on the exercise pressor reflex evoked by intermittent contraction of the triceps surae muscles in decerebrated, unanaesthetized rats. GsMTx4 reduced the pressor, cardioaccelerator and renal sympathetic nerve responses to intermittent contraction but did not reduce the pressor responses to femoral arterial injection of compounds that stimulate the metabolically-sensitive thin fibre muscle afferents. Expression levels of Piezo2 channels were greater than Piezo1 channels in rat dorsal root ganglia. Our findings suggest that mechanically-sensitive Piezo proteins contribute to the generation of the mechanical component of the exercise pressor reflex in rats. Mechanical and metabolic stimuli within contracting skeletal muscles evoke reflex autonomic and cardiovascular adjustments. In cats and rats, gadolinium has been used to investigate the role played by the mechanical component of this reflex, termed the exercise pressor reflex. Gadolinium, however, has poor selectivity for mechano-gated channels and exerts multiple off-target effects. We tested the hypothesis that GsMTX4, a more selective mechano-gated channel inhibitor than gadolinium and a particularly potent inhibitor of mechano-gated Piezo channels, reduced the exercise pressor reflex in decerebrate rats. Injection of 10 µg of GsMTx4 into the arterial supply of the hindlimb reduced the peak pressor (control: 24 ± 5, GsMTx4: 12 ± 5 mmHg, P < 0.01), cardioaccelerator and renal sympathetic nerve responses to tendon stretch, a purely mechanical stimulus, but had no effect on the pressor responses to intra-arterial injection of α,ß-methylene ATP or lactic acid. Moreover, injection of 10 µg of GsMTx4 into the arterial supply of the hindlimb reduced the peak pressor (control: 24 ± 2, GsMTx4: 14 ± 3 mmHg, P < 0.01), cardioaccelerator and renal sympathetic nerve responses to electrically-induced intermittent hindlimb muscle contractions. By contrast, injection of 10 µg of GsMTx4 into the jugular vein had no effect on the pressor, cardioaccelerator, or renal sympathetic nerve responses to contraction. Quantitative RT-PCR and western blot analyses indicated that both Piezo1 and Piezo2 channel isoforms were natively expressed in rat dorsal root ganglia tissue. We conclude that GsMTx4 reduced the exercise pressor reflex in decerebrate rats and that the reduction was attributable, at least in part, to its effect on mechano-gated Piezo channels.

Role played by interleukin-6 in evoking the exercise pressor reflex in decerebrate rats: effect of femoral artery ligation.

IL-6 signaling via the soluble IL-6 receptor (sIL-6r) has been shown to increase primary afferent responsiveness to noxious stimuli. This finding prompted us to test the hypothesis that IL-6 and sIL-6r would increase the exercise pressor reflex in decerebrate rats with freely perfused femoral arteries. We also tested the hypothesis that soluble glycoprotein (sgp)130, an inhibitor of IL-6/sIL-6r signaling, would decrease the exaggerated exercise pressor reflex that is found in decerebrate rats with ligated femoral arteries. In rats with freely perfused femoral arteries, coinjection of 50 ng of IL-6 and sIL-6r into the arterial supply of the hindlimb significantly increased the peak pressor response to static (control: 14 ± 3 mmHg and IL-6/sIL-6r: 17 ± 2 mmHg, P = 0.03) and intermittent isometric (control: 10 ± 2 mmHg and IL-6/sIL-6r: 15 ± 4 mmHg, P = 0.03) hindlimb muscle contraction. In rats with ligated femoral arteries, injection of 50 ng of sgp130 into the arterial supply of the hindlimb reduced the peak pressor response to static (control: 24 ± 2 mmHg and sgp130: 16 ± 3 mmHg, P = 0.01) and intermittent isometric (control: 16 ± 2 mmHg and sgp130: 13 ± 2 mmHg, P = 0.04) hindlimb muscle contraction, whereas there was no effect of sgp130 on the exercise pressor reflex in rats with freely perfused femoral arteries. We conclude that coinjection of exogenous IL-6 and sIL-6r increased the exercise pressor reflex in rats with freely perfused femoral arteries. More importantly, we also conclude that IL-6 and sIL-6r play an endogenous role in evoking the exercise pressor reflex in rats with ligated femoral arteries but not in rats with freely perfused femoral arteries.

The effects of dietary fish oil on exercising skeletal muscle vascular and metabolic control in chronic heart failure rats.

Impaired vasomotor control in chronic heart failure (CHF) is due partly to decrements in nitric oxide synthase (NOS) mediated vasodilation. Exercising muscle blood flow (BF) is augmented with polyunsaturated fatty acid (PUFA) supplementation via fish oil (FO) in healthy rats. We hypothesized that FO would augment exercising muscle BF in CHF rats via increased NO-bioavailability. Myocardial infarction (coronary artery ligation) induced CHF in Sprague-Dawley rats which were subsequently randomized to dietary FO (20% docosahexaenoic acid, 30% eicosapentaenoic acid, n = 15) or safflower oil (SO, 5%, n = 10) for 6-8 weeks. Mean arterial pressure (MAP), blood [lactate], and hindlimb muscles BF (radiolabeled microspheres) were determined at rest, during treadmill exercise (20 m·min(-1), 5% incline) and exercise + N(G)-nitro-l-arginine-methyl-ester (l-NAME) (a nonspecific NOS inhibitor). FO did not change left ventricular end-diastolic pressure (SO: 14 ± 2; FO: 11 ± 1 mm Hg, p > 0.05). During exercise, MAP (SO: 128 ± 3; FO: 132 ± 3 mm Hg) and blood [lactate] (SO: 3.8 ± 0.4; FO: 4.6 ± 0.5 mmol·L(-1)) were not different (p > 0.05). Exercising hindlimb muscle BF was lower in FO than SO (SO: 120 ± 11; FO: 93 ± 4 mL·min(-1)·100 g(-1), p < 0.05) but was not differentially affected by l-NAME. Specifically, 17 of 28 individual muscle BF's were lower (p < 0.05) in FO demonstrating that PUFA supplementation with FO in CHF rats does not augment muscle BF during exercise but may lower metabolic cost.

Impact of dietary nitrate supplementation via beetroot juice on exercising muscle vascular control in rats.

Dietary nitrate (NO(3)(-)) supplementation, via its reduction to nitrite (NO(2)(-)) and subsequent conversion to nitric oxide (NO) and other reactive nitrogen intermediates, reduces blood pressure and the O(2) cost of submaximal exercise in humans. Despite these observations, the effects of dietary NO(3)(-) supplementation on skeletal muscle vascular control during locomotory exercise remain unknown. We tested the hypotheses that dietary NO(3)(-) supplementation via beetroot juice (BR) would reduce mean arterial pressure (MAP) and increase hindlimb muscle blood flow in the exercising rat. Male Sprague-Dawley rats (3-6 months) were administered either NO(3)(-) (via beetroot juice; 1 mmol kg(-1) day(-1), BR n = 8) or untreated (control, n = 11) tap water for 5 days. MAP and hindlimb skeletal muscle blood flow and vascular conductance (radiolabelled microsphere infusions) were measured during submaximal treadmill running (20 m min(-1), 5% grade). BR resulted in significantly lower exercising MAP (control: 137 ± 3, BR: 127 ± 4 mmHg, P < 0.05) and blood [lactate] (control: 2.6 ± 0.3, BR: 1.9 ± 0.2 mm, P < 0.05) compared to control. Total exercising hindlimb skeletal muscle blood flow (control: 108 ± 8, BR: 150 ± 11 ml min(-1) (100 g)(-1), P < 0.05) and vascular conductance (control: 0.78 ± 0.05, BR: 1.16 ± 0.10 ml min(-1) (100 g)(-1) mmHg(-1), P < 0.05) were greater in rats that received BR compared to control. The relative differences in blood flow and vascular conductance for the 28 individual hindlimb muscles and muscle parts correlated positively with their percentage type IIb + d/x muscle fibres (blood flow: r = 0.74, vascular conductance: r = 0.71, P < 0.01 for both). These data support the hypothesis that NO(3)(-) supplementation improves vascular control and elevates skeletal muscle O(2) delivery during exercise predominantly in fast-twitch type II muscles, and provide a potential mechanism by which NO(3)(-) supplementation improves metabolic control.

Muscle oxygen transport and utilization in heart failure: implications for exercise (in)tolerance.

The defining characteristic of chronic heart failure (CHF) is an exercise intolerance that is inextricably linked to structural and functional aberrations in the O(2) transport pathway. CHF reduces muscle O(2) supply while simultaneously increasing O(2) demands. CHF severity varies from moderate to severe and is assessed commonly in terms of the maximum O(2) uptake, which relates closely to patient morbidity and mortality in CHF and forms the basis for Weber and colleagues' (167) classifications of heart failure, speed of the O(2) uptake kinetics following exercise onset and during recovery, and the capacity to perform submaximal exercise. As the heart fails, cardiovascular regulation shifts from controlling cardiac output as a means for supplying the oxidative energetic needs of exercising skeletal muscle and other organs to preventing catastrophic swings in blood pressure. This shift is mediated by a complex array of events that include altered reflex and humoral control of the circulation, required to prevent the skeletal muscle "sleeping giant" from outstripping the pathologically limited cardiac output and secondarily impacts lung (and respiratory muscle), vascular, and locomotory muscle function. Recently, interest has also focused on the dysregulation of inflammatory mediators including tumor necrosis factor-α and interleukin-1ß as well as reactive oxygen species as mediators of systemic and muscle dysfunction. This brief review focuses on skeletal muscle to address the mechanistic bases for the reduced maximum O(2) uptake, slowed O(2) uptake kinetics, and exercise intolerance in CHF. Experimental evidence in humans and animal models of CHF unveils the microvascular cause(s) and consequences of the O(2) supply (decreased)/O(2) demand (increased) imbalance emblematic of CHF. Therapeutic strategies to improve muscle microvascular and oxidative function (e.g., exercise training and anti-inflammatory, antioxidant strategies, in particular) and hence patient exercise tolerance and quality of life are presented within their appropriate context of the O(2) transport pathway.

Acute antioxidant supplementation and skeletal muscle vascular conductance in aged rats: role of exercise and fiber type.

Age-related increases in oxidative stress contribute to impaired skeletal muscle vascular control. However, recent evidence indicates that antioxidant treatment with tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) attenuates flow-mediated vasodilation in isolated arterioles from the highly oxidative soleus muscle of aged rats. Whether antioxidant treatment with tempol evokes similar responses in vivo at rest and during exercise in senescent individuals and whether this effect varies based on muscle fiber type composition are unknown. We tested the hypothesis that redox modulation via acute systemic tempol administration decreases vascular conductance (VC) primarily in oxidative hindlimb locomotor muscles at rest and during submaximal whole body exercise (treadmill running at 20 m/min, 5% grade) in aged rats. Eighteen old (25-26 mo) male Fischer 344 x Brown Norway rats were assigned to either rest (n = 8) or exercise (n = 10) groups. Regional VC was determined via radiolabeled microspheres before and after intra-arterial administration of tempol (302 µmol/kg). Tempol decreased mean arterial pressure significantly by 9% at rest and 16% during exercise. At rest, similar VC in 26 out of 28 individual hindlimb muscles or muscle parts following tempol administration compared with control resulted in unchanged total hindlimb muscle VC (control: 0.18 ± 0.02; tempol: 0.17 ± 0.05 ml·min(-1)·100 g(-1)·mmHg(-1); P > 0.05). During exercise, all individual hindlimb muscles or muscle parts irrespective of fiber type composition exhibited either an increase or no change in VC with tempol (i.e., ↑11 and ↔17 muscles or muscle parts), such that total hindlimb VC increased by 25% (control: 0.93 ± 0.04; tempol: 1.15 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1); P ≤ 0.05). These results demonstrate that acute systemic administration of the antioxidant tempol significantly impacts the control of regional vascular tone in vivo presumably via redox modulation and improves skeletal muscle vasodilation independently of fiber type composition during submaximal whole body exercise in aged rats.