Clinical and Experimental Pharmacology and Physiology (2003) 30, 559–564 Muscle Mechanics and Energetics: A Comparative View MEMBRANES AS METABOLIC PACEMAKERS Paul L Else* and Anthony J Hulbert † Metabolic Research Centre, Departments of *Biomedical and † Biological Sciences, University of Wollongong, Wollongong, New South Wales, Australia SUMMARY 1. In the present review, we suggest that a few common processes linked to membranes consume the majority of energy used by most organisms. 2. Membranes may act as metabolic pacemakers through changes in lipid composition, altering membrane character- istics and the working environment of membrane proteins. 3. Experiments involving membrane exchanges show pre- dictable changes in protein activities (sodium pump) that are dependent upon the type of membrane used. 4. Potential mechanisms discussed include fluidity, electrical fields, surface area requirements of lipids and peptide–lipid interactions. Key words: body size, development, ectothermy, endo- thermy, lipids, metabolism, molecular activity, Na + / K + - ATPase, sodium pump. INTRODUCTION Biology is laden with clever hypotheses and theories to explain the diversity and functioning of living organisms. Paramount in the generation of many of these ideas is the comparison of different species that provides the variation and models for investigation in all areas of biology. In this contribution, we show the value of the comparative approach in understanding the basic mechanisms underlying metabolism, specifically the role of membrane com- position. Over the past two decades, our work has concentrated on understanding the bases for metabolism. 1,2 During this time, we have used three comparative models of metabolism. The first is ectothermic (cold-blooded) and endothermic (warm-blooded) vertebrates, where body mass- and temperature-matched species commonly display fivefold differences in their weight-specific metabolism at the whole-animal level. 3 The second comparative model used has been that of body size, where small and large species within a class, such as mammals (shrew to elephant), show up to 100-fold differences in mass-specific metabolism. 4 The final model has been animal development, where, within a species (e.g. rat), two- to threefold differences in mass-specific organismal metabolism are common. 5 From the results of our own work using these models and those of many other researchers, three simple ideas have become clear. IDEAS The first idea is that a few processes consume the majority of energy used by most organisms. No major new cellular processes make up the differences in metabolism between organisms that can be in the order of 100-fold plus. Variation in functions performed by different organisms still involves the same basic energy consuming processes common to all organisms. In essence, there are many processes supported by a few energy consuming pro- cesses. For example, the sodium pump, a membrane-bound protein that actively regulates Na + /K + levels across cell membranes, under- pins numerous important and diverse physiological functions (e.g. nerve and muscle function, nutrient uptake, electrolyte reabsorp- tion or osmotic regulation that allows organisms such as the Nautilus to remove sea water from the chambers of its shell). The second idea is that the major energy consuming processes common to organisms account for similar proportions of total metabolism in animals with large differences in their overall rates of metabolism. As an example, the basic cost of living for mam- mals (using oxygen consumption as an overall measure) may be broken down into a small number of major energy consuming processes as shown in Table 1. Our studies and the work of others (for a review, see Hulbert and Else 6 ) would also support this as a general breakdown of metabolism for most vertebrates. The third idea is that the major energy consuming processes are either directly or indirectly associated with membranes. For some processes, this association is obvious and direct (e.g. Ca 2+ pumping and the proton pump leak cycle). For others, such as protein synthesis, the association is indirect, such as needed to move amino acids across membranes or in the functional association that ribosomes often share with membranes of the endoplasmic reticulum. HYPOTHESIS Combining these ideas we have developed a working hypothesis that we call the ‘membranes as pacemakers of metabolism hypo- Correspondence: Associate Professor PL Else, Department of Bio- medical Science, University of Wollongong, Northfields Avenue, Wollon- gong, NSW 2522, Australia. Email: pelse@uow.edu.au Presented at Muscle Mechanics and Energetics: A Comparative View, Melbourne, October 2002. The papers in these proceedings have been peer reviewed. Received 14 November 2002; revision 5 March 2003; accepted 8 March 2003.