Oxygen's double-edged sword: balancing muscle O2 supply and use during exercise.

When, approximately 3 billion years ago, cyanobacteria and other simple unicellular pro-karyocytes harnessed photosynthesis for energy metabolism they produced molecular O2 as a byproduct. Lethal for most contemporary anaerobic organisms, O2 fuelled the highly efficient mitochondrial energetics of emergent multicellular eukaryotes and sculpted Earth's flora and fauna thereafter. As atmospheric oxygen levels reached 10% (and fluctuated up to 30%) they powered the Cambrian explosion (542–488 million years ago) and complex multicellular organisms evolved at an unprecedented rate (Taylor & McElwain, 2010). However, distancing the atmospheric O2 source from its utilization in tissue mitochondria required development of complex highly integrated organ systems dedicated to supporting respiration (i.e. O2 supply and removal of carbon dioxide). Across the animal kingdom evolution has shaped the genome around the double-edged sword of this O2 transport problem: minimizing harmful effects of too much O2 (i.e. hyperoxia, leading to tissue damage via reactive O2 species) or too little O2 (i.e. hypoxia, see Taylor & McElwain, 2010). For mammals in particular, the maximal capacity for O2 transport and utilization () and the system dynamics (or kinetics, i.e. rapidity of change), in response to altered metabolic demands have been optimized. Regarding this crucial issue, Grassi and colleagues (2011) provide original evidence that muscle creatine kinase (CK) constitutes a locus of control for kinetics in mammalian muscle. Humans have recognized O2's presence and its sentinel role in respiration for less than four centuries. In the early 17th century, the apothecary Michael Sendivogius of Poland produced O2 by heating potassium nitrate (saltpetre, 2KNO3→ 2KNO2+ O2) (Szydlo, 1994). The remarkable and secretive Dutch engineer and scientist Cornelis Jacobszoon Drebbel recognized that air was a mixture of gases and purified what he called the ‘spirituous part of it that makes it fit for respiration.’ In 1621 Drebbel demonstrated to King James I that his ‘liquor’ (presumably O2) could sustain up to 12 men in a submarine for 1–3 h as they navigated the River Thames from Westminster to Greenwich (a distance of ∼7 miles): this a century and a half before Joseph Priestley, Carl Wilhelm Sheele and Antoine Laurent Lavoisier's ‘discovery’ and naming of oxygen ∼1774! For generations of physiologists has been considered the defining characteristic of the O2 transport system. However, animals and humans rarely, and then only fleetingly, exercise at . In contrast, daily life with all its physical activities embodies frequent metabolic transitions. The speed of one's kinetics defines such transitions with respect to minimizing intramuscular perturbations (i.e. Δ[PCr], [ADPfree], [H+], [glycogen]), and supporting muscle energetics and exercise tolerance (Poole et al. 2008). In young healthy individuals cycling or running, kinetics control resides in the muscle mitochondria in contrast to O2 delivery. Accordingly, whereas advancing age or the predations of disease may move the site of that control upstream into the O2 transport pathway, compelling evidence in healthy animals and humans supports that increasing muscle O2 delivery does not speed kinetics, nor do modest decreases slow kinetics (Poole et al. 2008). Thus, the delivery of sufficient O2 to contracting muscle when the muscle O2 demands are changing most rapidly ensures adequate microvascular O2 partial pressure () to support capillary-myocyte O2 flux and kinetics (Behnke et al. 2002). The elegant CK blockade (by iodoacetamide) experiments by Grassi et al. (2011) demonstrate, for the first time in an ‘intact’ mammalian muscle preparation, that CK can play a deterministic role in kinetics control (see also Whipp & Mahler, 1980). Specifically, by providing an energetic buffer the CK system preserves [ATP] close to resting at the expense of [CP] and allows to increase more slowly than otherwise. This kinetics control may be crucial for ensuring that O2 demands () do not outstrip O2 delivery and thereby compromise microvascular and capillary–myocyte O2 flux. A further intriguing observation, that CK blockade compromises muscle contractile ability and enhances fatigability, suggests that muscle function can be grossly impaired despite speeding kinetics. This contrasts markedly with faster kinetics found in the presence of increased muscle mitochondrial volume density and [CK] post-exercise training (Whipp & Mahler, 1980; Jones & Poole, 2005). Finally, that muscle contractile efficiency can be modulated at the level of CK has major implications for individuals in whom chronic disease has lowered systemic and muscle(s) O2 transport and therefore exercise capacity. The ability to accomplish 20 or 30% more work for the same ATP demand (and therefore ) may, for these individuals, translate to increased mobility and independence thereby enhancing life quality. In summary, Grassi and colleagues’ findings indicate that CK provides a locus of control for at least two parameters of aerobic function, kinetics and contractile efficiency. Design of therapeutic interventions targeting CK may improve muscle and exercise function in patient populations who are compromised by low limiting muscle O2 transport or pathologically slowed kinetics. Future experimental efforts might explore how this could be accomplished whilst maintaining microvascular values adequately to support capillary–myocyte O2 flux yet avoiding the pernicious effects of too much O2 (hyperoxia) or impaired muscle contractile activity.