Regulation of skeletal muscle blood flow during exercise in ageing humans

Abstract

The regulation of skeletal muscle blood flow and oxygen delivery to contracting skeletal muscle is complex and involves the mechanical effects of muscle contraction; local metabolic, red blood cell and endothelium-derived substances; and the sympathetic nervous system (SNS). With advancing age in humans, skeletal muscle blood flow is typically reduced during dynamic exercise and this is due to a lower vascular conductance, which could ultimately contribute to age-associated reductions in aerobic exercise capacity, a primary predictor of mortality in both healthy and diseased ageing populations. Recent findings have highlighted the contribution of endothelium-derived substances to blood flow control in contracting muscle of older adults. With advancing age, impaired nitric oxide availability due to scavenging by reactive oxygen species, in conjunction with elevated vasoconstrictor signalling via endothelin-1, reduces the local vasodilatory response to muscle contraction. Additionally, ageing impairs the ability of contracting skeletal muscle to blunt sympathetic vasoconstriction (i.e. 'functional sympatholysis'), which is critical for the proper regulation of tissue blood flow distribution and oxygen delivery, and could further reduce skeletal muscle perfusion during high intensity and/or large muscle mass exercise in older adults. We propose that initiation of endothelium-dependent hyperpolarization is the underlying signalling event necessary to properly modulate sympathetic vasoconstriction in contracting muscle, and that age-associated impairments in red blood cell adenosine triphosphate release and stimulation of endothelium-dependent vasodilatation may explain impairments in both local vasodilatation and functional sympatholysis with advancing age in humans.

Figure 1. Age‐associated impairments in functional sympatholysis

A, sympathetic vasoconstrictor responses to cold pressor test (CPT) during moderate intensity cycle exercise were greater in older relative to young men (%ΔFVC: −14 ± 3% vs. −2 ± 4%, respectively; P < 0.05; FVC: forearm vascular conductance). B, similarly, vasoconstrictor responses (assessed as decreases in skeletal muscle oxygenation) during sympathetic stimulation via lower body negative pressure (LBNP) were not blunted during moderate intensity handgrip exercise compared with resting conditions in older women, and were greater during exercise compared with young women (*P < 0.05 vs. Rest within condition). C, postjunctional α₂‐adrenoceptor stimulation (via intra‐arterial clonidine) reduced vascular conductance similarly in resting skeletal muscle of young and older men during infusion of the vasodilator adenosine (filled bars). In contrast, vasoconstrictor responses during moderate intensity handgrip exercise were greater in older men relative to young men (open bars) (^† P < 0.05 vs. Adenosine within condition; *P < 0.05 vs. Young). The collective data demonstrate impaired modulation of sympathetic α‐adrenoceptor vasoconstriction in contracting muscle of older adults. From Koch et al. (2003), Fadel et al. (2004) and Dinenno et al. (2005).

Figure 2. Lack of an obligatory role for NO, PGs, K_IR channels, or Na⁺/K⁺‐ATPase in mediating functional sympatholysis in healthy humans

In young adults, vasoconstrictor responses to phenylephrine (PE; α₁‐adrenoceptor agonist) in resting tissue during infusion of adenosine (ADO) as a high flow control condition and moderate intensity handgrip exercise (15% maximum voluntary contraction (MVC)). Combined inhibition of nitric oxide (NO; l‐NMMA)_, prostaglandins (PGs; ketorolac), inwardly rectifying potassium channels (K_IR channels; BaCl₂), and Na⁺/K⁺‐ATPase (oubain) had no effect on the exercise‐induced attenuation of vasoconstriction in response to PE (*P < 0.05 vs. ADO within condition; ^† P < 0.05 vs. Control; ^‡ P < 0.05 vs. l‐NMMA+ketorolac). From Crecelius et al. (2015 b).

Figure 3. Modulation of α₁‐mediated vasoconstriction during exercise and ATP infusions in young and older adults

Vasoconstrictor responses to phenylephrine (PE; α₁‐adrenoceptor agonist) during passive vasodilatation with adenosine, moderate handgrip exercise (15% MVC), and passive vasodilatation with adenosine triphosphate (ATP). A, vasoconstrictor responsiveness in resting skeletal muscle during infusion of adenosine was attenuated in older adults, whereas vasoconstriction was greater in older adults during handgrip exercise. ATP blunted vasoconstriction similarly in both young and older adults. B and C, magnitude of sympatholysis, describing the ability of contracting skeletal muscle to blunt sympathetic vasoconstriction, is impaired in older adults during exercise (B), but maintained during exogenous ATP infusions (C). The percentage magnitude of sympatholysis was calculated as ((%FVC adenosine − %FVC exercise or ATP)/%FVC adenosine) × 100. (^§ P < 0.05 vs. Young within condition; ^† P < 0.05 vs. Adenosine within age group; ^‡ P < 0.05 vs. Exercise within age group). From Kirby et al. (2011).

Figure 4. Working hypothesis: contribution of ATP to functional sympatholysis in young and older adults

A, young, red blood cells (RBCs) traversing the microcirculation of contracting skeletal muscle encounter areas of high oxygen demand resulting in diffusion of oxygen to the active tissue, desaturation of haemoglobin, and subsequent release of the potent vasodilator adenosine triphosphate (ATP). Locally, ATP binds to purinergic receptors (P_2y) located on the endothelial cell (EC), which elevates intracellular calcium, in turn activating iK_Ca and sK_Ca channels (calcium activated potassium channels, K_ca) resulting in efflux of potassium (K⁺) and hyperpolarization of the endothelium. Endothelium‐derived hyperpolarization (EDH) conducts bi‐directionally, away from the local signal, along the endothelium through gap junctions (GJ) and spreads directly to the vascular smooth muscle cells (VSMC) through myoendothelial gap junctions (MEGJ). The effect of EDH on VSMC tone is twofold, causing vasodilatation as well as blunting sympathetic vasoconstriction, thus facilitating distribution of blood flow and oxygen to areas of high metabolic demand. B, older, while exogenous ATP is still capable of evoking vasodilatation and can blunt sympathetic vasoconstriction in older adults (denoted as small grey arrows), impaired endogenous ATP release from RBCs may result in reduced local and conducted vasodilatation, as well as an impaired ability to modulate sympathetic vasoconstriction in contracting muscle. These impairments may result in attenuated bulk blood flow delivery to, and inefficient distribution within, contracting skeletal muscle of older adults. Θ Indicates hyperpolarization.