Blood flow restriction without sympathetic vasoconstriction in ageing skeletal muscle during exercise

Advancing age (e.g. >60 years) inevitably makes it harder to perform daily activities. Thus, a question central to the effects of ageing on physical performance concerns the changes underlying the loss of function. While muscle mass typically declines with advanced age, limitations of muscle blood flow have been documented in older vs. younger subjects otherwise matched in muscle mass and body composition. During the last two decades, leading investigators in exercise physiology have established that the activity of the sympathetic nervous system is enhanced during advanced age in association with the reduction in skeletal muscle blood flow. However, in this issue of The Journal, a laboratory recognized for its insightful studies of blood flow regulation in humans provides a new explanation that contrasts with prevailing dogma that reduced skeletal muscle blood flow reflects enhanced sympathetic vasoconstriction (Richards et al. 2014). When considering how this dogma evolved, the stage is set for identifying gaps in our understanding as well as providing alternative explanations. In comparing younger (mid-20s) with older endurance-trained men and women (60–65 years old), deficiencies in maximal oxygen uptake and blood flow to leg muscles during submaximal cycling were identified in the late 1990s (Proctor et al. 1998). Even when normalized to muscle mass, maximal oxygen uptake and vascular conductance were ∼25% lower in older compared with younger subjects. Furthermore, higher work rates were associated with nearly 2-fold greater levels of noradrenaline ‘spillover’ in the femoral venous blood of older vs. younger subjects. In complementary experiments on healthy older and younger subjects studied in resting conditions, blood flow to the leg was ∼25% lower in older subjects despite no difference in fat-free tissue mass between age groups (Dinenno et al. 1999). Across subjects, the reduction in femoral artery blood flow and vascular conductance was significantly correlated with elevated vascular resistance and muscle sympathetic nerve activity (SNA). Thus, reduced blood flow to skeletal muscle in older adults has come to be associated with an ‘elevated sympathetic vasoconstrictor state’. Sympathetic vasoconstriction results from noradrenaline released from perivascular nerves acting postsynaptically on two adrenoreceptor (AR) subtypes expressed on vascular smooth muscle cells: α1ARs and α2ARs. During treadmill exercise in dogs, intra-arterial infusion of prazosin to inhibit α1ARs in the hindlimb vasculature increased muscle blood flow and vascular conductance as workload increased (O'Leary et al. 1997), indicating progressively greater restraint of vasodilatation by the sympathetic nervous system during exercise. Such exemplary findings are consistent with enhanced SNA during ageing as the basis of restricted muscle blood flow. Complementary protocols in humans have used pharmacological interventions to investigate how ageing affected sympathetic vasoconstriction during exercise. For example, reductions in forearm blood flow during α1AR activation (via intra-arterial infusion of phenylephrine) were blunted in older vs. younger males, while blood flow reductions in response to α2AR activation with clonidine infusion were similar between age groups (Dinenno et al. 2002). Thus, attenuated reductions in forearm blood flow in older vs. younger men during tyramine infusion (to evoke release of endogenous noradrenaline) were attributed to reduced responsiveness of α1ARs. During tyramine infusion into the femoral artery, reductions in leg blood flow were also attenuated in older vs. younger men and attributed to the attenuation of both α1AR- and α2AR-mediated responses with ageing (Smith et al. 2007). Nevertheless, a concern raised by such findings is that whilst SNA may be enhanced with advanced age, the responsiveness of the vasculature to αAR activation is diminished concomitantly. Thus, an alternative explanation for reduced muscle blood flow during exercise with advanced age appears warranted. A key experimental factor that had been lacking in studies of human subjects is now illustrated with the insightful studies of Richards et al. (2014). In older vs. younger men and women, the effect of non-selective αAR blockade (via phentolamine infusion) on brachial artery blood flow and vascular conductance was investigated at rest and during rhythmic hand-grip exercise of mild to moderate intensity. Although no difference was apparent between age groups at rest, blood flow restriction with diminished vascular conductance prevailed in older vs. younger subjects during exercise. Remarkably, in the presence of αAR blockade, blood flow and conductance during exercise remained significantly lower in older vs. younger subjects. While SNA was not evaluated in these experiments, the age-associated restraint of muscle blood flow and vascular conductance could not be explained by enhanced sympathetic vasoconstriction. The forearm musculature is a relatively small muscle mass compared with that engaged in running or cycling. A key advantage of this model is that it is not limited by systemic regulation of blood pressure or cardiac output and thereby provides insight into whether impairments exist in local vasomotor control. Consistent with findings from several laboratories, older subjects exhibited depressed endothelium-dependent vasodilatation in response to acetylcholine (Richards et al. 2014). Thus, impaired availability of (or responsiveness to) locally produced vasodilators may contribute to reductions in vascular conductance during exercise with advanced age. As regional differences (e.g. legs vs. arms) have been observed in sympathetic modulation of vascular conductance, and given the dependence of SNA on exercise intensity and active muscle mass, further studies are warranted to determine whether the findings of Richards et al. (2014) during hand-grip exercise are applicable to more intense exercise involving greater muscle mass and the lower extremities.