Heterogeneous ageing of skeletal muscle microvascular function

Abstract

The distribution of blood flow to skeletal muscle during exercise is altered with advancing age. Changes in arteriolar function that are muscle specific underlie age-induced changes in blood flow distribution. With advancing age, functional adaptations that occur in resistance arterioles from oxidative muscles differ from those that occur in glycolytic muscles. Age-related adaptations of morphology, as well as changes in both endothelial and vascular smooth muscle signalling, differ in muscle of diverse fibre type. Age-induced endothelial dysfunction has been reported in most skeletal muscle arterioles; however, unique alterations in signalling contribute to the dysfunction in arterioles from oxidative muscles as compared with those from glycolytic muscles. In resistance arterioles from oxidative muscle, loss of nitric oxide signalling contributes significantly to endothelial dysfunction, whereas in resistance arterioles from glycolytic muscle, alterations in both nitric oxide and prostanoid signalling underlie endothelial dysfunction. Similarly, adaptations of the vascular smooth muscle that occur with advancing age are heterogeneous between arterioles from oxidative and glycolytic muscles. In both oxidative and glycolytic muscle, late-life exercise training reverses age-related microvascular dysfunction, and exercise training appears to be particularly effective in reversing endothelial dysfunction. Patterns of microvascular ageing that develop among muscles of diverse fibre type and function may be attributable to changing patterns of physical activity with ageing. Importantly, aerobic exercise training, initiated even at an advanced age, restores muscle blood flow distribution patterns and vascular function in old animals to those seen in their young counterparts.

Figure 1. Mechanisms of age‐induced endothelial dysfunction differ in arterioles from the soleus muscle, primarily composed of high‐oxidative fibres, and the white portion of the gastrocnemius muscle, primarily composed of glycolytic fibres

In soleus muscle arterioles, endothelial dysfunction is largely attributable to loss of availability of BH4, eNOS uncoupling, and imbalance between NO and O₂ ⁻ generation. In gastrocnemius muscle arterioles, loss of both COX and eNOS signalling leads to impaired endothelial dilatation and loss of endothelial modulation of vasoconstrictor signalling. BH4: tetrahydrobiopterin; eNOS: endothelial nitric oxide synthase; O₂ ⁻: superoxide anion.

Figure 2. Mechanisms of age‐induced vascular smooth muscle dysfunction differ in arterioles from the soleus muscle, primarily composed of high‐oxidative fibres, and the white portion of the gastrocnemius muscle, primarily composed of glycolytic fibres

In soleus muscle arterioles, increased signalling through Kv and KCa channels and remodelling of the vascular wall contribute to impaired myogenic constriction. In gastrocnemius muscle arterioles, increased signalling through Kv, but not KCa channels, contributes to impaired myogenic constriction, and increased signalling through ETA receptors underlies heightened ET‐mediated vasoconstriction. In arterioles from both the soleus and gastrocnemius muscles, reduced signalling through β‐adrenergic receptors leads to reduced isoproterenol‐mediated vasodilatation. Kv: voltage‐gated potassium channel; KCa: Ca²⁺‐activated potassium channel; ETA: endothelin type A receptor.

Figure 3. Age induces redistribution of blood flow within the gastrocnemius muscle

In aged rats during exercise, blood flow is redistributed away from the red,oxidative portion of the muscle to the white, glycolytic portion of the muscle. Exercise training reverses this redistribution of flow, so that in old exercise trained rats, blood flow to the red and white portions of the gastrocnemius muscle during exercise are not discernible from blood flow to these portions of the gastrocnemius muscle of young rats. Modified from Behnke et al. (2012). Y RG, young red gastrocnemius; Y WG, young white gastrocnemius; O RG, old red gastrocnemius; O WG, old white gastrocnemius; YEX RG, young exercise trained red gastrocnemius; YEX WG, young exercise trained white gastrocnemius; OEX RG, old exercise trained red gastrocnemius; OEX WG, old exercise trained white gastrocnemius.