Skeletal muscle microvascular oxygenation dynamics in heart failure: exercise training and nitric oxide-mediated function

Abstract

Chronic heart failure (CHF) impairs nitric oxide (NO)-mediated regulation of skeletal muscle O2 delivery-utilization matching such that microvascular oxygenation falls faster (i.e., speeds PO2mv kinetics) during increases in metabolic demand. Conversely, exercise training improves (slows) muscle PO2mv kinetics following contractions onset in healthy young individuals via NO-dependent mechanisms. We tested the hypothesis that exercise training would improve contracting muscle microvascular oxygenation in CHF rats partly via improved NO-mediated function. CHF rats (left ventricular end-diastolic pressure = 17 ± 2 mmHg) were assigned to sedentary (n = 11) or progressive treadmill exercise training (n = 11; 5 days/wk, 6-8 wk, final workload of 60 min/day at 35 m/min; -14% grade downhill running) groups. PO2mv was measured via phosphorescence quenching in the spinotrapezius muscle at rest and during 1-Hz twitch contractions under control (Krebs-Henseleit solution), sodium nitroprusside (SNP; NO donor; 300 μM), and N(G)-nitro-l-arginine methyl ester (L-NAME, nonspecific NO synthase blockade; 1.5 mM) superfusion conditions. Exercise-trained CHF rats had greater peak oxygen uptake and spinotrapezius muscle citrate synthase activity than their sedentary counterparts (p < 0.05 for both). The overall speed of the PO2mv fall during contractions (mean response time; MRT) was slowed markedly in trained compared with sedentary CHF rats (sedentary: 20.8 ± 1.4, trained: 32.3 ± 3.0 s; p < 0.05), and the effect was not abolished by L-NAME (sedentary: 16.8 ± 1.5, trained: 31.0 ± 3.4 s; p > 0.05). Relative to control, SNP increased MRT in both groups such that trained CHF rats had slower kinetics (sedentary: 43.0 ± 6.8, trained: 55.5 ± 7.8 s; p < 0.05). Improved NO-mediated function is not obligatory for training-induced improvements in skeletal muscle microvascular oxygenation (slowed PO2mv kinetics) following contractions onset in rats with CHF.

Endurance, interval sprint, and resistance exercise training: impact on microvascular dysfunction in type 2 diabetes

“…Hirai and colleagues (59) reported that, in healthy rats, progressive moderate to vigorous downhill running endurance EX improved microvascular oxygenation profiles following the onset of skeletal muscle contraction, partially through an NO mechanism. Furthermore, similar improvements were observed in rats with chronic heart failure but did not appear to be NO mediated (60). Interestingly, in the aforementioned studies, EX augmented soleus and red gastrocnemius citrate synthase content, but only in the latter study did citrate synthase content increase in the spinotrapezius muscle, the skeletal muscle where microvascular oxygenation was examined.…”

Exercise training in chronic heart failure: improving skeletal muscle O2transport and utilization

“…Remarkably, that no substantial impairments in Hct cap were detected across the rest-contraction transient in HFrEF indicates that effective capillary surface area at any given time was lowered in approximate proportion to the reduction in capillaries sustaining RBC flow. Taken together, these investigations demonstrate that HFrEF is associated with pronounced impairments in skeletal muscle transcapillary O 2 flux via reductions in both diffusive (i.e., D mO 2 ; 2number of RBC flowing capillaries per unit muscle width x ↔Hct cap ) and convective (i.e., Q mO 2 ; 2number of RBC flowing capillaries per unit muscle width x 2f RBC ) conductances (162,257 (30,58,59,65,78,136,206) are thus associated with impairments in mitochondrial energetics and contractile performance (138,164,294,323).…”

“…In addition, blockade of nitric oxide synthase (NOS) by nitro-L-arginine methyl ester (L-NAME) reveals that the NOS contribution to Q mO 2 -to-V mO 2 matching in healthy muscle is substantially reduced in HFrEF. As the NOS enzymes are upregulated by exercise training (134,136; for a review, see Ref. 188), this, in addition to reduced oxidative stress, decreased sympathetic and humorally mediated vasoconstriction, and improved vascularity (capillary and arteriolar; see Fig.…”

“…2, 33, 43, 61,72,74,97,112,115,136,156,226,267,307,309) reflecting that the key signaling pathways for mitochondrial biogenesis and function, such as PGC-1␣ and calcineurin activation, are preserved in the skeletal muscle of CHF patients (90). Nonetheless, there are reports to the contrary (90,160,274,289,305,319,340).…”

“…Key questions posed in the 2012 review (248) have been addressed; especially regarding the plasticity of Q mO 2 in response to exercise training and novel therapeutic strategies. For instance, in contrast to healthy animals it is now apparent that exercise training in CHF (reduced ejection fraction) acts to raise P mvO 2 , in part, via non-NO-mediated effects (134,136). Additionally, inorganic nitrate supplementation (NO source) has proven to be especially effective in raising blood flow (Q m ) and Q mO 2 to fast-twitch muscle fibers in healthy animals (76, 77) and improving cardiac output, V O 2max , and exercise capacity in CHF patients (CHF with preserved ejection fraction; Ref.…”