Heterogeneity of blood flow: impact of age on muscle specific tissue perfusion during exercise.

Age-related physiological changes occur in every organ system. While many of these processes are well described, alterations that occur with age in regard to exercise performance and fatigability are not straightforward. Using a reductionist approach the examination of muscle energetics may serve as an ideal starting point to further understand age-related alterations in exercise capacity. Simply defined, muscle energetics is the conversion of chemical to mechanical energy, and is fundamental in the understanding of muscle contraction and human performance. While a thorough discussion of factors effecting muscle energetics with age is beyond the scope of this commentary, the role of blood flow and the evidence in support of age-associated reductions in blood flow may provide valuable insight into exercise performance with age. Specifically, muscle blood flow plays a critical role in muscle energetics and fatigue due to the importance of oxygen and nutrient delivery and removal of metabolic by-products. Hence, reductions in blood flow would be expected to accelerate fatigue, while the contrary may also be true such that improvements in blood flow thwart fatigue. With this information as background the study by Rudroff et al. (2014), recently published in The Journal of Physiology, examined muscle blood flow and blood flow heterogeneity during fatiguing contractions of the knee extensor muscles in healthy young and older men. Before diving too deep into the findings it is important to understand the experimental paradigm and technique used by Rudroff et al., (2014) as these factors undoubtedly impact the interpretation and generalizability of the study. To assess blood flow the authors employed positron emission tomography (PET) imaging. Compared to more conventional techniques (Doppler ultrasound, thermodilution, plethysmography), PET imaging offers a unique opportunity to evaluate blood flow distribution, or heterogeneity, which yields a specific and local assessment of tissue perfusion during exercise. Conversely, the more conventional techniques are unable to distinguish between whole-limb and tissue specific blood flow. With regard to the experimental paradigm, the healthy older men were characterized as life-long exercisers, an important distinction when considering the reduction in physical activity that typically accompanies the aging process. A more appropriate description of these older men may be older-trained; however, in keeping with the terminology used by Rudroff et al. (2014) and to avoid confusion we simply refer to this unique group as older. Importantly, this life-long sustained physical activity may account for the matching of muscle strength and endurance in the young and old despite a 30% smaller knee extensor muscle volume in the latter. Lastly, the authors chose to assess blood flow during a prolonged (>20 min) isometric knee extension exercise, which has some bearing on the generalization of the results. With the intricacies of the experimental paradigm discussed we move to the main findings of the study. The authors report that the older men exhibited a greater perfusion per gram of tissue during the fatiguing exercise task when compared to the young men. Moreover, this elevated perfusion is more uniformly distributed within the working muscles of the older men as evidenced by reduced blood flow heterogeneity. The elevation in muscle blood flow per unit of tissue mass coupled with a more uniform distribution of blood flow may appear paradoxical. However, upon further consideration, the elevated perfusion is likely to be appropriate as the older men performed a similar task with a 30% smaller muscle mass, thus matching blood flow to the level of contractile work. Echoing the findings of Rudroff et al. (2014), we recently documented augmented limb blood flow during dynamic plantarflexion exercise that is likely to be due to a concomitant elevation in the in vivo ATP cost of contraction as estimated by 31P magnetic resonance spectroscopy (Layec et al. 2014). Rudroff et al. (2014) also examined blood flow in the antagonist knee flexor muscles and observed that the older subjects adopted an inefficient strategy to accomplish the isometric task as they actively recruited and perfused antagonistic knee flexor muscles. Increasing antagonist muscle activation likely increased the load on the agonist muscles during the isometric task which may, in part, explain the greater blood flow per gram of muscle in the old. The remainder of this commentary will provide critical evaluation and discussion of the findings of Rudroff et al. (2014) while focusing on a few key topics centred on the interaction of blood flow, efficiency, fatigability, and aging. Rudroff and colleagues are quick to acknowledge the difficulty in stating that aging is or is not associated with increased fatigability. The underlying mechanisms contributing to force production and fatigue development are substantially different between isometric and dynamic contractions and are further confounded by age. Specific to this point, the development of fatigue in the young and old was similar during the isometric task. This finding confirms accumulating evidence suggesting an age-related preservation, or even improvement, in fatigue resistance during isometric tasks, possibly occurring as a result of slowed contractile properties and greater myofilament stiffness leading to greater force generation during isometric contractions (Miller & Toth, 2013). However, unique to the study by Rudroff et al. (2014) was the finding that, despite a similar absolute level of force during knee extension, tissue perfusion was enhanced in the quadriceps of older individuals. Although not directly measured, the elevated tissue perfusion may lead to an enhanced O2 delivery, thus accounting for the similar fatigability between groups during isometric exercise and the greater contribution of oxidative phosphorylation to ATP synthesis commonly reported in older individuals during isometric contractions in isolated muscle (Tevald et al. 2010). Alternatively, the elevated tissue perfusion may be a compensatory mechanism to counter attenuated O2 extraction observed during exercise in the old (Poole et al. 2003). Based on the above discussion, the findings from Rudroff et al. (2014) appreciably improve our understanding of the mechanisms underpinning the greater resistance to fatigue during isometric contraction with age. However, it also raises the question with more insistence of whether O2 delivery and blood flow redistribution to active muscle contribute to impaired exercise tolerance with age during dynamic contractions. Indeed, this mode of contraction is more relevant to activities of daily living and has been associated with greater fatigue development in older individuals. Paradoxically, available evidence suggests that the age-related adaptations in the function of the myofilament that appear to be beneficial during isometric contraction may, in fact, be deleterious during dynamic contractions. For instance, the slowing of the cross-bridge kinetics with age would not only result in longer contraction time during dynamic exercise (increasing ATP demand and the cost per contraction), but would also prolong the contraction-induced compression of the small vessels impairing O2 delivery and by-product removal for a longer period during each contraction, potentially affecting ATP-generating pathways during exercise. Besides these alterations in contractile efficiency, an impaired mitochondrial coupling has also been previously described in the quadriceps of older individuals during exercise, suggesting profound alterations in muscle efficiency with advancing age that are not counteracted by a shift in fibre type toward a slower phenotype. Given the key role played by muscle efficiency in exercise capacity, it is intriguing that muscle performance and fatigue were actually similar between young and older individuals. However, this might stem from the very low intensity employed and the isometric nature of the contraction, which might have lessened the metabolic differences between the young and the older subjects as this mode of contraction is less demanding from a metabolic standpoint. This is confirmed by the tissue perfusion value reported in the quadriceps, which was only ∼10 ml min−1 (100 g)−1 in both groups at the end of the exercise. This aspect of the protocol does not diminish the significance of the findings of Rudroff et al. (2014), but emphasizes the need for future studies investigating dynamic exercise across a range of intensities. Rudroff and colleagues report that healthy older individuals exhibit greater perfusion per gram of tissue and improved blood flow distribution during isometric fatiguing exercise. This is an important and interesting finding that provides insight into age-related alterations in exercise capacity while simultaneously creating a plethora of questions that remain to be answered. Future research in this area is warranted to assess the relationship between blood flow distribution, muscle metabolism and fatigability during dynamic exercise with age. Along these lines a group of older inactive subjects characterized by increased fatigability would provide important insight into whether blood flow is in fact a key player in fatigue.