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Journal Article•DOI•

Does intracellular metabolite diffusion limit post-contractile recovery in burst locomotor muscle?

Stephen T. Kinsey1, Pragyansri Pathi2, Kristin M. Hardy1, Amanda Jordan2, Bruce R. Locke2 •
University of North Carolina at Wilmington1, Florida A&M University – Florida State University College of Engineering2
15 Jul 2005-The Journal of Experimental Biology (J Exp Biol)-Vol. 208, Iss: 14, pp 2641-2652
TL;DR: It is concluded that fiber SA:V and O2 flux exert more control than intracellular metabolite diffusive flux over the developmental changes in metabolic organization and metabolic fluxes that characterize these muscles.
Abstract: Post-metamorphic growth in the blue crab entails an increase in body mass that spans several orders of magnitude. The muscles that power burst swimming in these animals grow hypertrophically, such that small crabs have fiber diameters that are typical of most cells ( 600·µm). Thus, as the animals grow, their muscle fibers cross and greatly exceed the surface area to volume ratio (SA:V) and intracellular diffusion distance threshold that is adhered to by most cells. Large fiber size should not impact burst contractile function, but post-contractile recovery may be limited by low SA:V and excessive intracellular diffusion distances. A number of changes occur in muscle structure, metabolic organization and metabolic flux during development to compensate for the effects of increasing fiber size. In the present study, we examined the impact of intracellular metabolite diffusive flux on the rate of postcontractile arginine phosphate (AP) resynthesis in burst locomotor muscle from small and large animals. AP recovery was measured following burst exercise, and these data were compared to a mathematical reaction‐diffusion model of aerobic metabolism. The measured rates of AP resynthesis were independent of fiber size, while simulations of aerobic AP resynthesis yielded lower rates in large fibers. These contradictory findings are consistent with previous observations that there is an increased reliance on anaerobic metabolism for post-contractile metabolic recovery in large fibers. However, the model results suggest that the interaction between mitochondrial ATP production rates, ATP consumption rates and diffusion distances yield a system that is not particularly close to being limited by intracellular metabolite diffusion. We conclude that fiber SA:V and O2 flux exert more control than intracellular metabolite diffusive flux over the developmental changes in metabolic organization and metabolic fluxes that characterize these muscles.

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Citations
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Journal Article•DOI•
Scaling with body mass of mitochondrial respiration from the white muscle of three phylogenetically, morphologically and behaviorally disparate teleost fishes.

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Jessica L. Burpee1, Elise L. Bardsley1, Richard M. Dillaman1, Wade O. Watanabe1, Stephen T. Kinsey1 •
University of North Carolina at Wilmington1
12 May 2010-Journal of Comparative Physiology B-biochemical Systemic and Environmental Physiology
TL;DR: The size-independence of VO2mt indicates that differences in WM aerobic function result from variation in Vmt and not to changes inVO2mt, consistent with prior work that indicated that while diffusion constraints influence mitochondrial distribution, the negative scaling of aerobic processes like post-contractile PCr recovery can largely be attributed to the body size dependence of Vmt.
Abstract: White muscle (WM) fibers in many fishes often increase in size from 250 μm in adults. This leads to increases in intracellular diffusion distances that may impact the scaling with body mass of muscle metabolism. We have previously found similar negative scaling of aerobic capacity (mitochondrial volume density, V(mt)) and the rate of an aerobic process (post-contractile phosphocreatine recovery) in fish WM. In the present study, we examined the scaling with body mass of oxygen consumption rates of isolated mitochondria (VO(2mt)) from WM in three species from different families that vary in morphology and behavior: an active, pelagic species (bluefish, Pomatomus saltatrix), a relatively inactive demersal species (black sea bass, Centropristis striata), and a sedentary, benthic species (southern flounder, Paralichthys lethostigma). In contrast to our prior studies, the measurement of respiration in isolated mitochondria is not influenced by the diffusion of oxygen or metabolites. V(mt) was measured in WM and in high-density isolates used for VO(2mt) measurements. WM V(mt) was significantly higher in the bluefish than in the other two species and VO(2mt) was independent of body mass when expressed per milligram protein or per milliliter mitochondria. The size-independence of VO(2mt) indicates that differences in WM aerobic function result from variation in V(mt) and not to changes in VO(2mt). This is consistent with our prior work that indicated that while diffusion constraints influence mitochondrial distribution, the negative scaling of aerobic processes like post-contractile PCr recovery can largely be attributed to the body size dependence of V(mt).

26 citations

Cites background or result from "Does intracellular metabolite diffu..."

  • ..., ATP) diffusion between mitochondria influences metabolic rate (Hardy et al. 2006; Jimenez et al. 2008; Kinsey et al. 2005), and in isolated muscle, where O2 was maintained at high levels to eliminate the influence of O2 diffusion on the rate of metabolism (Nyack et al....

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  • ...…to the mitochondria and metabolite (e.g., ATP) diffusion between mitochondria influences metabolic rate (Hardy et al. 2006; Jimenez et al. 2008; Kinsey et al. 2005), and in isolated muscle, where O2 was maintained at high levels to eliminate the influence of O2 diffusion on the rate of…...

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  • ...This is consistent with reaction–diffusion models that showed that the rates of aerobic processes in muscle are generally not limited by diffusion (Hardy et al. 2009; Kinsey et al. 2005; 2007; Locke and Kinsey, 2008; Nyack et al. 2007)....

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Scaling of anaerobic energy metabolism during tail flipping behaviour in the fresh water crayfish, Cherax destructor

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John Baldwin, Asha Gupta, Ximena Iglesias
01 Jan 1998
TL;DR: The positive allometry of anaerobic capacity observed for enforced exercise may not be used routinely in nature because of metabolic constraints imposed during recovery, and may involve inhibition of glycolytic enzymes at low pH, and the scaling of intracellular pH buffering.
Abstract: The allometry of anaerobic metabolism during escape behaviour was examined in the freshwater crayfish, Cherax destructor. Exercise time to exhaustion, and the total number of tail flips, increased with body mass. Concentrations of arginine phosphate and glycogen in the tail musculature of resting-state animals were independent of body mass, as was glycogen concentration following exercise to exhaustion. Lactate produced during exhaustive exercise, and intracellular pH buffering capacity, showed positive allometry. Activities of phosphorylase, phosphofructokinase and lactate dehydrogenase in the tail musculature showed positive allometry, while arginine kinase activity was independent of body mass. The positive allometry of anaerobic scope, reflected in the scaling of glycolytic enzyme activities, scales with the increased power required by larger animals to overcome drag during locomotion through water. The increased capacity for anaerobic muscle work in larger animals scales with anaerobic glycolytic capacity, while the contribution from phosphagen hydrolysis remains constant. Limits to anaerobic capacity are not set by fuel stores, but may involve inhibition of glycolytic enzymes at low pH, and the scaling of intracellular pH buffering. The positive allometry of anaerobic capacity observed for enforced exercise may not be used routinely in nature because of metabolic constraints imposed during recovery.

21 citations

Journal Article•DOI•
A reaction–diffusion analysis of energetics in large muscle fibers secondarily evolved for aerobic locomotor function

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Kristin M. Hardy1, Bruce R. Locke2, Marilia Da Silva2, Stephen T. Kinsey1•
University of North Carolina at Wilmington1, Florida A&M University – Florida State University College of Engineering2
15 Sep 2006-The Journal of Experimental Biology
TL;DR: Examining the impact of intracellular metabolite diffusive flux on the rate of post-contractile AP resynthesis in the dark muscle suggests that high ATP turnover rates may lead to diffusion limitation in muscle even when diffusion distances are short, as in the subdivided dark fibers.
Abstract: The muscles that power swimming in the blue crab, Callinectes sapidus, grow hypertrophically, such that in juvenile crabs the cell diameters are <60 microm, whereas fibers of the adult crabs often exceed 600 microm. Thus, as these animals grow, their muscle fibers greatly exceed the surface area to volume ratio and intracellular diffusion distance limits of most cells. Previous studies have shown that arginine phosphate (AP) recovery in the anaerobic (light) fibers, which demonstrate a fiber size dependence on anaerobic processes following contraction, is too slow to be restricted by intracellular metabolite diffusive flux, in spite of the fiber's large size. By contrast, the aerobic (dark) fibers have evolved an intricate network of intracellular subdivisions that maintain an effectively small ;metabolic diameter' throughout development. In the present study, we examined the impact of intracellular metabolite diffusive flux on the rate of post-contractile AP resynthesis in the dark muscle, which has a much higher aerobic capacity than the light muscle. AP recovery was measured for 60 min in adults and 15 min in juveniles following burst contractile activity in dark fibers, and a mathematical reaction-diffusion model was used to test whether the observed aerobic rates of AP resynthesis were fast enough to be limited by intracellular metabolite diffusion. Despite the short diffusion distances and high mitochondrial density, the AP recovery rates were relatively slow and we found no evidence of diffusion limitation. However, during simulation of steady-state contraction, which is an activity more typical of the dark fibers, there were substantial intracellular metabolite gradients, indicative of diffusion limitation. This suggests that high ATP turnover rates may lead to diffusion limitation in muscle even when diffusion distances are short, as in the subdivided dark fibers.

17 citations

Cites background or methods or result from "Does intracellular metabolite diffu..."

  • ...Additionally, glycogen depletion (Boyle et al., 2003), lactate accumulation (Johnson et al., 2004) and AP depletion (Kinsey et al., 2005) (see below) during exercise were identical in muscle fibers from juvenile and adult crabs, indicating a uniform metabolic response to stimulated exercise....

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  • ...(Kinsey et al., 2005) used the same mathematical reaction–diffusion model used in the present study to investigate whether diffusion was limiting to AP recovery in the blue crab anaerobic light muscle; a fiber with extreme proportions, but a relatively low aerobic capacity (and hence low rate of ATP production)....

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  • ...…recruited following burst contractions in large anaerobic fibers to accelerate certain key phases of recovery that would otherwise be slowed by size-related limitations to the rate of aerobic ATP synthesis (Kinsey and Moerland, 2002; Boyle et al., 2003; Johnson et al., 2004; Kinsey et al., 2005)....

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  • ...This is not surprising considering that AP recovery rates in dark fibers were similar to those found previously for light fibers (Kinsey et al., 2005), although it is likely that a less intense exercise protocol may have allowed higher recovery rates in dark fibers by reducing lactate production (see above)....

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  • ...(Kinsey et al., 2005), with parameters adjusted to comply with blue crab dark levator fibers....

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Journal Article•DOI•
Recovery periods of cultured spiny lobster, Sagmariasus verreauxi juveniles: Effects of handling, force feeding, exercising to exhaustion and anaesthesia on oxygen consumption and ammonia-N excretion rates

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Mark A. Jensen1, Quinn P. Fitzgibbon1, Chris G. Carter1, Louise R. Adams2•
University of Tasmania1, Australian Maritime College2
10 Oct 2013-Aquaculture
TL;DR: It is demonstrated that lobsters recover rapidly from handling and the increase in M ˙ O 2 induced by 2-phenoxyethanol demonstrated this is not an effective anaesthetic for reducing recovery periods and physiological stress associated with handling.

17 citations

Journal Article•DOI•
Reaction–diffusion constraints in living tissue: Effectiveness factors in skeletal muscle design

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Santosh K. Dasika1, Stephen T. Kinsey2, Bruce R. Locke1•
Florida A&M University – Florida State University College of Engineering1, University of North Carolina at Wilmington2
01 Jan 2011-Biotechnology and Bioengineering
TL;DR: None of the fibers was strongly limited by diffusion, as expected, and most were well within the domain of reaction control of aerobic metabolic rate, which may constitute a safety factor in muscle that provides a level of protection from diffusion constraints under conditions such as hypoxia.
Abstract: A mathematical model was developed to analyze the effects of intracellular diffusion of O2 and high-energy phosphate metabolites on aerobic energy metabolism in skeletal muscle. We tested the hypotheses that in a range of muscle fibers from different species (1) aerobic metabolism was not diffusion limited and (2) that fibers had a combination of rate and fiber size that placed them at the brink of substantial diffusion limitation. A simplified chemical reaction rate law for mitochondrial oxidative phosphorylation was developed utilizing a published detailed model of isolated mitochondrial function. This rate law was then used as a boundary condition in a reaction–diffusion model that was further simplified using the volume averaging method and solved to determine the rates of oxidative phosphorylation as functions of the volume fraction of mitochondria, the size of the muscle cell, and the amount of oxygen delivered by the capillaries. The effectiveness factor, which is the ratio of reaction rate in the system with finite rates of diffusion to those in the absence of any diffusion limitations, defined the regions where intracellular diffusion of metabolites and O2 may limit aerobic metabolism in both very small, highly oxidative fibers as well as in larger fibers with lower aerobic capacity. Comparison of model analysis with experimental data revealed that none of the fibers was strongly limited by diffusion, as expected. However, while some fibers were near substantial diffusion limitation, most were well within the domain of reaction control of aerobic metabolic rate. This may constitute a safety factor in muscle that provides a level of protection from diffusion constraints under conditions such as hypoxia. Biotechnol. Bioeng. 2011; 108:104–115. © 2010 Wiley Periodicals, Inc.

16 citations

Cites result from "Does intracellular metabolite diffu..."

  • ...A number of fibers, regardless of aerobic capacity, tend to reside in positions on the surface that are near a significant decrease in h, which is similar to findings in our prior work (Jimenez et al., 2008; Kinsey et al., 2005) and consistent with the second part of Weisz’s hypothesis....

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  • ...A number of fibers, regardless of aerobic capacity, tend to reside in positions on the surface that are near a significant decrease in h, which is similar to findings in our prior work (Jimenez et al., 2008; Kinsey et al., 2005) and consistent with the second part of Weisz’s hypothesis....

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References
More filters
Book•
Scaling, why is animal size so important?

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Knut Schmidt-Nielsen
01 Jan 1984
TL;DR: The importance of animal size in animal function is discussed in this paper, where it is shown that physical laws are equally important, for they determine rates of diffusion and heat transfer, transfer of force and momentum, strength of structures, the dynamics of locomotion, and other aspects of the functioning of animal bodies.
Abstract: This book is about the importance of animal size. We tend to think of animal function in chemical terms and talk of water, salts, proteins, enzymes, oxygen, energy, and so on. We should not forget, however, that physical laws are equally important, for they determine rates of diffusion and heat transfer, transfer of force and momentum, the strength of structures, the dynamics of locomotion, and other aspects of the functioning of animal bodies. Physical laws provide possibilities and opportunities for an organism, yet they also impose constraints, setting limits to what is physically possible. This book aims to give an understanding of these rules because of their profound implications when we deal with animals of widely different size and scale. The reader will find that the book raises many questions. Remarkable and puzzling information makes it read a little like a detective story, but the last chapter, instead of giving the final solution, neither answers all questions nor provides one great unifying principle.

2,736 citations

Journal Article•DOI•
Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis.

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Theo Wallimann1, Markus Wyss1, Dieter Brdiczka2, Klaas Nicolay3, Hans M. Eppenberger1 •
École Polytechnique Fédérale de Lausanne1, University of Konstanz2, Utrecht University3
01 Jan 1992-Biochemical Journal

1,940 citations

"Does intracellular metabolite diffu..." refers background in this paper

  • ...The intracellular diffusive flux of high-energy phosphates is largely mediated by phosphagen kinases, such as creatine kinase (CK) and arginine kinase (AK), although the mechanistic details are still the subject of study (reviewed by Walliman et al., 1992; Ellington, 2001)....

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Journal Article•DOI•
A linear model of muscle respiration explains monoexponential phosphocreatine changes

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Ronald A. Meyer1•
Michigan State University1
01 Apr 1988-American Journal of Physiology-cell Physiology
TL;DR: Phosphocreatine content was measured by phosphorus nuclear magnetic resonance spectroscopy in the gastrocnemius muscles of pentobarbital-anesthetized rats during and after twitch stimulation to be consistent with a simple first-order electrical analog model of oxidative metabolism that is applicable at submaximal oxidative rates.
Abstract: Phosphocreatine (PCr) content was measured by phosphorus nuclear magnetic resonance spectroscopy in the gastrocnemius muscles of pentobarbital-anesthetized rats during and after twitch stimulation at rates up to 0.75 Hz. The monoexponential time constant for PCr changes was similar at the onset of vs. during recovery after stimulation and was not significantly different for different stimulation rates (mean time constant 1.44 min). Steady-state PCr level during stimulation was linearly related to the product of stimulation rate times peak twitch force. These results are shown to be consistent with a simple first-order electrical analog model of oxidative metabolism that is applicable at submaximal oxidative rates. The model assumes equilibrium of the creatine kinase reaction, which is modeled as a chemical capacitor, with capacitance proportional to the total creatine level, and PCr level proportional to the cytosolic free energy of ATP hydrolysis.

504 citations

"Does intracellular metabolite diffu..." refers methods in this paper

  • ...This approach has been effectively employed to describe some of the major processes of energy metabolism in muscle, and a variety of kinetic models have been developed that closely match experimental data (e.g. Meyer, 1988; Jeneson et al., 1995; Vicini and Kushmerick, 2000; Korzeniewski, 2003)....

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Journal Article•DOI•
A simple analysis of the "phosphocreatine shuttle"

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R. A. Meyer, H. L. Sweeney, Martin J. Kushmerick
01 May 1984-American Journal of Physiology-cell Physiology
TL;DR: Experimental results demonstrating the transport aspects of the CK reaction emphasize only one feature of a more general notion of facilitated diffusion by near-equilibrium metabolic reactions and do not per se establish the existence of any physical or functional compartmentation of ATP, ADP, PCr, or creatine.
Abstract: The diffusive mobility of solutes chemically connected by reversible reactions in cells is analyzed as a problem of facilitated diffusion. By this term we mean that the diffusive flux of any substance, X, which is in one metabolic pathway, is effectively increased when it participates in a second and equilibrium reaction with another substance Y because the total flux of X in the pathway is the sum of the fluxes of X and Y. This notion is generalized and is seen to include the familiar enhanced intracellular diffusion of oxygen by oxymyoglobin. In this framework the function of creatine kinase (CK) is seen to have two aspects: 1) phosphocreatine (PCr) via the CK reaction buffers the cellular ATP and ADP concentrations and 2) transport of high-energy phosphates is predominantly in the chemical form of PCr. This predominance of PCr is a consequence of the maintained ATP, ADP, and total creatine levels and of the apparent equilibrium constant of the reaction. Thus experimental results demonstrating the transport aspects of the CK reaction emphasize only one feature of a more general notion of facilitated diffusion by near-equilibrium metabolic reactions and do not per se establish the existence of any physical or functional compartmentation of ATP, ADP, PCr, or creatine. PCr can be a large source for increasing inorganic phosphate levels during contractile activity, possibly as a metabolic regulator. Neither the transport nor buffer aspects can be quantitatively important in cells with small distances between ATP-utilizing and ATP-generating sites, such as is the case with cardiac myofibrils and mitochondria.

497 citations

"Does intracellular metabolite diffu..." refers background or methods in this paper

  • ...These are likely to include systems with relatively high rates of ATP production/consumption and distant sites of ATP utilization, such as in some muscle fibers with a higher aerobic capacity than examined here (Meyer et al., 1984; Stokes and Josephson, 1992; Vendelin et al., 2000; Saks et al., 2003; Suarez, 2003) or in the flagellum of spermatozoa, which has been the subject of many reaction–diffusion analyses (e....

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  • ...…metabolism found theoretical evidence for concentration gradients in high-energy phosphate molecules during steady-state contraction in muscle (Mainwood and Rakusan, 1982; Meyer et al., 1984; Hubley et al., 1997; Aliev and Saks, 1997; Kemp et al., 1998; Vendelin et al., 2000; Saks et al., 2003)....

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  • ...The mitochondrial boundary conditions at x=0 balance the fluxes of ATP and ADP into the bulk phase with the rates of formation and consumption at the mitochondria and are modeled using Michaelis-Menten kinetics with ADP activation (Meyer et al., 1984):...

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  • ...A Km,mito value for ADP of 20·µmol·l–1 was used, which is within the range for fast skeletal muscle (Meyer et al., 1984)....

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  • ...…the bulk phase with the rates of formation and consumption at the mitochondria and are modeled using Michaelis-Menten kinetics with ADP activation (Meyer et al., 1984): where RmitoATP and RmitoADP are the boundary reaction rates for ATP and ADP, respectively, Vm,mito is the maximal velocity…...

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Journal Article•DOI•
Evolution and physiological roles of phosphagen systems

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W R Ellington1•
Florida State University1
01 Jan 2001-Annual Review of Physiology
TL;DR: It is hypothesized that the capacity for intracellular targeting of CK evolved early as a means of facilitating energy transport in highly polarized cells and was subsequently exploited for temporal ATP buffering and dynamic roles in metabolic regulation in cells displaying high and variable rates of aerobic energy production.
Abstract: Phosphagens are phosphorylated guanidino compounds that are linked to energy state and ATP hydrolysis by corresponding phosphagen kinase reactions: phosphagen + MgADP + H(+) guanidine acceptor + MgATP. Eight different phosphagens (and corresponding phosphagen kinases) are found in the animal kingdom distributed along distinct phylogenetic lines. By far, the creatine phosphate/creatine kinase (CP/CK) system, which is found in the vertebrates and is widely distributed throughout the lower chordates and invertebrates, is the most extensively studied phosphagen system. Phosphagen kinase reactions function in temporal ATP buffering, in regulating inorganic phosphate (Pi) levels, which impacts glycogenolysis and proton buffering, and in intracellular energy transport. Phosphagen kinase reactions show differences in thermodynamic poise, and the phosphagens themselves differ in terms of certain physical properties including intrinsic diffusivity. This review evaluates the distribution of phosphagen systems and tissue-specific expression of certain phosphagens in an evolutionary and functional context. The role of phosphagens in regulation of intracellular Pi levels likely evolved early. Thermodynamic poise of the phosphagen kinase reaction profoundly impacts this capacity. Furthermore, it is hypothesized that the capacity for intracellular targeting of CK evolved early as a means of facilitating energy transport in highly polarized cells and was subsequently exploited for temporal ATP buffering and dynamic roles in metabolic regulation in cells displaying high and variable rates of aerobic energy production.

472 citations

"Does intracellular metabolite diffu..." refers background in this paper

  • ...The intracellular diffusive flux of high-energy phosphates is largely mediated by phosphagen kinases, such as creatine kinase (CK) and arginine kinase (AK), although the mechanistic details are still the subject of study (reviewed by Walliman et al., 1992; Ellington, 2001)....

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Related Papers (5)
A model for intracellular energy transport.

[...]

01 Jan 1982-Canadian Journal of Physiology and Pharmacology
G. W. Mainwood, K. Rakusan
The long and winding road: influences of intracellular metabolite diffusion on cellular organization and metabolism in skeletal muscle.

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15 Oct 2007-The Journal of Experimental Biology
Stephen T. Kinsey, Kristin M. Hardy, Bruce R. Locke
A simple analysis of the "phosphocreatine shuttle"

[...]

01 May 1984-American Journal of Physiology-cell Physiology
R. A. Meyer, H. L. Sweeney, Martin J. Kushmerick
Diffusional anisotropy is induced by subcellular barriers in skeletal muscle.

[...]

01 Feb 1999-NMR in Biomedicine
Stephen T. Kinsey, Bruce R. Locke, Bruce R. Locke, Brigita Penke, Timothy S. Moerland 
Reduction in muscle fibre number during the adaptive radiation of notothenioid fishes: a phylogenetic perspective.

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01 Aug 2003-The Journal of Experimental Biology
Ian A. Johnston, Daniel Alfredo Fernández, Jorge Calvo, Vera L. A. Vieira, Anthony W. North, Marguerite Abercromby, Theodore Garland