On being the right size: heart design, mitochondrial efficiency and lifespan potential.

1. From the smallest shrew or bumble-bee bat to the largest blue whale, heart size varies by over seven orders of magnitude (from 12 mg to 600 kg). This study reviews the scaling relationships between heart design, cellular bioenergetics and mitochondrial efficiencies in mammals of different body sizes. 2. The [31P]-nuclear magnetic resonance-derived [phosphocreatine]/[ATP] ratio in hearts of smaller mammals is significantly higher (2.7 +/- 0.3 for mouse; n = 22) than in larger mammals (1.6 +/- 0.3 for humans; n = 13). 3. The inverse of the free myocardial cytosolic [ADP] concentration and the cytosolic phosphorylation ratio ([ATP]/[ADP][Pi]) scales with heart size and with absolute mitochondrial and myofibrillar volumes, close to a quarter-power (from -0.22 to -0.28; r = 0.99). 4. Assuming a similar mitochondrial P/O ratio and the same maximal amount of work required to convert 1 mol NADH to 0.5 mol O2 (i.e. 212.25 kJ/mol), the higher [ATP]/[ADP][Pi] ratios or cellular driving forces (DeltaG'ATP) in hearts of smaller mammals imply greater mitochondrial efficiencies in coupling ATP production to electron transport as body size decreases. For a P/O ratio of 2.5, the mitochondrial efficiency in the heart of a shrew, mouse, human and whale is 84, 82, 71 and 65%, respectively. 5. Higher cytosolic ATP]/[ADP][Pi] ratios and DeltaG'ATP values imply that the hearts of smaller mammals operate further from equilibrium than hearts of larger mammals. 6. As a consequence of scaling relationships, a number of remarkable invariants emerge when comparing heart function from the smallest shrew to the largest whale; the total volume of blood pumped by each heart in a lifetime is approximately 200 million L/kg heart and the total number of heart beats is approximately 1.1 billion per lifetime. 7. Similarly, the metabolic potential (total O2 consumed during adult lifespan per g bodyweight) for a 2 g shrew or a 100000 kg blue whale is approximately 38 L O2 consumed or 8.5 mol ATP/g body mass per lifetime. 8. The importance of quarter-power scaling relationships linking structural, metabolic and bioenergetic design to the natural ageing process and maximum lifespan potential is discussed.