Matching of O2 Utilization and O2 Delivery in Contracting Skeletal Muscle in Health, Aging, and Heart Failure

Abstract

Skeletal muscle is one of the most dynamic metabolic organs as evidenced by increases in metabolic rate of >150-fold from rest to maximal contractile activity. Because of limited intracellular stores of ATP, activation of metabolic pathways is required to maintain the necessary rates of ATP re-synthesis during sustained contractions. During the very early phase, phosphocreatine hydrolysis and anaerobic glycolysis prevails but as activity extends beyond ∼1 min, oxidative phosphorylation becomes the major ATP-generating pathway. Oxidative metabolism of macronutrients is highly dependent on the cardiovascular system to deliver O2 to the contracting muscle fibres, which is ensured through a tight coupling between skeletal muscle O2 utilization and O2 delivery. However, to what extent O2 delivery is ideal in terms of enabling optimal metabolic and contractile function is context-dependent and determined by a complex interaction of several regulatory systems. The first part of the review focuses on local and systemic mechanisms involved in the regulation of O2 delivery and how integration of these influences the matching of skeletal muscle O2 demand and O2 delivery. In the second part, alterations in cardiovascular function and structure associated with aging and heart failure, and how these impact metabolic and contractile function, will be addressed. Where applicable, the potential of exercise training to offset/reverse age- and disease-related cardiovascular declines will be highlighted in the context of skeletal muscle metabolic function. The review focuses on human data but also covers animal observations.

Regulation of the microvasculature during small muscle mass exercise in chronic obstructive pulmonary disease vs. chronic heart failure

“…D SM O 2 is an estimate of oxygen transport capacity from the capillary to the mitochondria ( Østergaard, 2020 ). It comprises a convective component and a diffusive component, of which the latter depends on the total capillary wall area available for diffusion during red blood cell passage, reflecting the total number of perfused capillaries and their length, the capillary flow distribution, spatial distribution of capillaries and potential structural changes in the diffusion membrane ( Wagner, 2000 ; Poole, 2019 ; Nyberg and Jones, 2022 ). The relative interdependence of convection and diffusion is difficult to establish during human muscle contractions.…”

The ‘normal’ adjustment of oxygen delivery to small muscle mass exercise is not optimized for muscle contractile function

“…To date, adequate oxygen delivery demand matching has been described by Nyberg and Jones (2022) from the perspective of the 'tipping point' hypothesis proposed by Poole et al (2008). That is, if oxygen delivery exceeds demand, an increase or minor decrease in oxygen delivery will not change oxygen uptake (i.e.…”

“…Hogan et al, 1992Hogan et al, , 1999. Therefore, although V O 2 is maintained at a decreased oxygen delivery, inferring adequate oxygen delivery according to the criteria presented by Nyberg and Jones (2022), this oxygen delivery is not optimal for muscle contractile function.…”

“…In a recent review, Nyberg and Jones (2022) frame adequate oxygen delivery demand matching as follows: if delivery is adequate to support $${V_{{O_2}}}$$, then increasing oxygen delivery will not increase $${V_{{O_2}}}$$. This interpretation appears to hold up at intensities below critical power (Pawelczyk et al., 1992).…”

“…The caveat to this response is that the increased metabolic disturbance at the same $${V_{{O_2}}}$$ compromises force at a given muscle activation (Fulco et al., 1996; Hogan et al., 1992, 1999). Therefore, although $${V_{{O_2}}}$$ is maintained at a decreased oxygen delivery, inferring adequate oxygen delivery according to the criteria presented by Nyberg and Jones (2022), this oxygen delivery is not optimal for muscle contractile function.…”