The Role of Muscle Perfusion in the Age-Associated Decline of Mitochondrial Function in Healthy Individuals

Abstract

Maximum oxidative capacity of skeletal muscle measured by in vivo phosphorus magnetic resonance spectroscopy ( 31 P-MRS) declines with age, and negatively affects whole-body aerobic capacity. However, it remains unclear whether the loss of oxidative capacity is caused by reduced volume and function of mitochondria or limited substrate availability secondary to impaired muscle perfusion. Therefore, we sought to elucidate the role of muscle perfusion on the age-related decline of muscle oxidative capacity and ultimately whole-body aerobic capacity. Muscle oxidative capacity was assessed by 31 P-MRS post-exercise phosphocreatine recovery time (τ PCr ), with higher τ PCr reflecting lower oxidative capacity, in 75 healthy participants (48 men, 22–89 years) of the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing study. Muscle perfusion was characterized as an index of blood volume at rest using a customized diffusion-weighted MRI technique and analysis method developed in our laboratory. Aerobic capacity (peak-VO 2 ) was also measured during a graded treadmill exercise test in the same visit. Muscle oxidative capacity, peak-VO 2 , and resting muscle perfusion were significantly lower at older ages independent of sex, race, and body mass index (BMI). τ PCr was significantly associated with resting muscle perfusion independent of age, sex, race, and BMI ( p -value = 0.004, β = −0.34). τ PCr was also a significant independent predictor of peak-VO 2 and, in a mediation analysis, significantly attenuated the association between muscle perfusion and peak-VO 2 (34% reduction for β in perfusion). These findings suggest that the age-associated decline in muscle oxidative capacity is partly due to impaired muscle perfusion and not mitochondrial dysfunction alone. Furthermore, our findings show that part of the decline in whole-body aerobic capacity observed with aging is also due to reduced microvascular blood volume at rest, representing a basal capacity of the microvascular system, which is mediated by muscle oxidative capacity. This finding suggests potential benefit of interventions that target an overall increase in muscle perfusion for the restoration of energetic capacity and mitochondrial function with aging.

Moderate‐to‐Vigorous Physical Activity Is Associated With Higher Muscle Oxidative Capacity in Older Adults

“…Indeed, this result remains important because it demonstrates that, although MVPA is strongly associated with muscle oxidative capacity, some other unknown effects of age negatively affect mitochondrial function via mechanisms that are not fully offset by higher levels of MVPA. 3,28,29 These findings contrast with previously published results, suggesting that the decline in mitochondrial function with aging is explained by an age-associated reduction of physical activity. 8,11 This discrepancy may be due to the small sample size of fewer than 40 participants in these previous studies.…”

In vivo assessment of mitochondrial capacity using NIRS in locomotor muscles of young and elderly males with similar physical activity levels

“…In the VL, a 25% slower mVȮ 2 recovery in older individuals was observed, reflecting a decrease in mitochondrial capacity with age. This finding is in agreement with studies measuring PCr recovery in the VL (Conley et al 2000;Johannsen et al 2012;Larsen et al 2012;Choi et al 2016;Adelnia et al 2019) and with studies measuring ex vivo oxygen consumption using high-resolution respirometry (Porter et al 2015;Distefano et al 2018). Specifically, Larsen et al found a 23% decrease in PCr recovery in older adults compared to younger adults in a similar-aged and physical activity-matched population (Larsen et al 2012).…”

“…This is supported by recent research, which reported that ageing was associated with a decrease in resting muscle perfusion in middle-aged and elderly adults. Resting muscle perfusion rates were negatively associated with muscle PCr recovery and whole-body oxidative capacity, suggesting that changes in reperfusion could affect physical functioning with advancing age (Adelnia et al 2019). However, in that study, the population was not matched for physical activity, making it again difficult to draw conclusions from the results.…”

Proteomic signatures of in vivo muscle oxidative capacity in healthy adults

“…Because of the fundamental dependence of mammalian life on adequate mitochondrial function, we searched for proteins patterns that could provide clues about resilience mechanisms aimed at maintaining mitochondrial function in spite of damage accumulation. We elected to focus on healthy adults spanning a wide age range, selected with strict inclusion criteria as being healthy (Adelnia et al, ; Ubaida‐Mohien, Lyashkov, et al, ), to allow for a robust assessment of underlying biological mechanisms associated with oxidative capacity independent of the confounding effect of diseases. After adjusting for age, habitual physical activity, sex, race, BMI, and muscle fiber type ratio, a subset of 253 out of 4,300 muscle proteins were significantly associated with better oxidative capacity of skeletal muscle.…”

“…We used data from 49 subjects from the Genetic and Epigenetic Study of Aging and Laboratory Testing (GESTALT) study and another 8 subjects from the Baltimore Longitudinal Study of Aging. Inclusion criteria for all participants were those of the GESTALT study (Adelnia et al, ; Ubaida‐Mohien, Lyashkov, et al, ). Briefly, participants were required to be free of major diseases or cognitive or physical impairment, with the exception of controlled hypertension.…”