Shaken and stirred: muscle structure and metabolism

Abstract

Muscle fibers, specialized for the conversion of chemical energy into mechanical work, are some of the most highly structured cells known. Muscles perform diverse mechanical functions, ranging from the maintenance of posture and the propulsion of blood, to the movement of limbs for locomotion. They display the largest changes in metabolic rate when undergoing transitions between rest and exercise, as well as the highest metabolic flux rates known in the animal kingdom. From these perspectives, muscles are ideal models for probing the relationships between cell structure and metabolism.In cardiac and locomotory muscles, the transition from rest to exercise is accompanied by an increase in the rate of cellular ATP hydrolysis, brought about by the activation of actomyosin ATPase and, to a variable extent, Ca 2+ -ATPase and Na + -K + -ATPase. Bioenergetic pathways are regulated such that ATP is synthesized at rates that match hydrolysis rates. The stoichiometric matching of rates of synthesis and hydrolysis allows the maintenance of contractile function. Bouts of exercise may vary in both duration and intensity, and many species of animals possess fiber types specialized in structure and biochemical properties to serve their particular needs.Brief (e.g. 1-2·s) bouts of exercise may be accompanied by the Muscles are ideal models with which to examine the relationship between structure and metabolism because they are some of the most highly structured cells, and are capable of the largest and most rapid metabolic transitions as well as the highest metabolic rates known. Studies of metabolism have traditionally been conducted within what can considered as the kinetic paradigm provided by 'solution biochemistry'; i.e. the rates of enzymatic reactions are studied in terms of their regulation by mass-action and allosteric effectors and, most recently, metabolic control analysis of pathways. This approach has served biology well and continues to be useful. Here, we consider the diffusion of small and large molecules in muscles and energy metabolism in the context of intracellular space. We find that in attempting to explain certain phenomena, a purely kinetic paradigm appears insufficient. Instead, phenomena such as the 'shuttling' of high-energy phosphate donors and acceptors and the binding of metabolic enzymes to intracellular structures or to each other are better understood when metabolic rates and their regulation are considered in the context of intracellular compartments, distances, gradients and diffusion. As in all of biology, however, complexity dominates, and to such a degree that one pathway may consist of several reactions that each behave according to different rules. 'Soluble' creatine kinase operates at or near equilibrium, while mitochondrial and myofibrillar creatine kinases directly channel substrate to (or from) the adenine nucleotide translocase and actomyosin-ATPase, their operation being thus displaced from equilibrium. Hexose 6-phosphate metabolism appears to obey the rules of solution biochemistry...

Flux control and excess capacity in the enzymes of glycolysis and their relationship to flight metabolism inDrosophila melanogaster

“…In these conditions, flux rates may depart significantly from expectations of simple solution biochemistry (55), and many glycolytic enzymes may be diffusion-limited and therefore require close proximity to operate under high flux (56). Studies in Drosophila of glycerol-3-phosphate dehydrogenase, GAPDH, TPI, phosphoglycerate kinase, phosphoglycerol mutase, and aldolase point to a structured muscle cell environment in which enzymes ''colocalize'' (53,54) and removal of a member causes others to disassociate.…”

Molecules in motion: influences of diffusion on metabolic structure and function in skeletal muscle

“…Rather, we are summarizing the movement of intracellular molecules and other probes where D has been measured without these confounding effects, in order to evaluate the nature of the intrafiber environment. In addition, it is possible that intracellular convection associated with contraction may enhance intracellular transport (Hochachka, 1999;Suarez et al, 2003). There has been limited experimental testing of this hypothesis, although the D of several proteins was not increased by muscle contraction or passive stretching and shortening (Baylor and Pape, 1988;Papadopoulos et al, 2000).…”

“…Federspiel, 1986;Groebe, 1995;Hoofd and Egginton, 1997;Piiper, 2000;Lai et al, 2007;Dash et al, 2008), and there are a number of reviews of aspects of O 2 and aerobic substrate transport to mitochondria in muscle (e.g. Hoppeler and Weibel, 1998;Wagner, 2000;Suarez, 2003;Weibel and Hoppeler, 2004). Some conclusions from past work are that (1) control of O 2 flux to, and usage by, mitochondria is shared among the various steps in the O 2 cascade, (2) a substantial decrease in P O2 occurs between the capillary and the fiber, and (3) intracellular O 2 gradients may be present.…”

Molecular population genetics and selection in the glycolytic pathway

“…They also must accommodate twice the flux rate because of the split of hexose 6-phosphate into triose phosphate. This has lead to the proposal that these downstream enzymes have evolved colocalization and possible channeling to facilitate flux under conditions of high metabolic demand (Suarez, 2003). The implications of these other properties to metabolic control and the evolution of the enzymes across the pathway are unclear.…”