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The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle.

Cooke R - Biophys Rev (2011)

Bottom Line: Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle.In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding.Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry & Biophysics, Cardiovascular Research Institute, University of California, Box 2240, Genentech Hall, 600, 6th Street, San Francisco, CA 94158-2517 USA.

ABSTRACT
Resting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the "furnace" that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430-435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.

No MeSH data available.


Related in: MedlinePlus

Fluorescence intensities are shown as a function of time during the chase phase of two single-nucleotide turnover experiments in permeable rabbit fast-twitch muscle fibers. The fluorescence decay occurring during a chase with ATP following an incubation with mantATP [2′-/3′-O-(N′-methylanthraniloyl)-ATP] is shown (red, open circles). The rise in fluorescence intensity occurring during the inverse experiment in which the fiber was first incubated with ATP followed by a chase with mantATP is also shown (blue, open squares). The composition of the incubation and chase phases are shown above, color-coded with the data. The fluorescence changes in two phases, a rapid phase which has a time constant of approximately 20 s followed by a slow phase with a time constant of 230 s. The slower phase is attributed to the slow release of nucleotides from a fraction of myosin heads, which are in a “super relaxed” state. Reproduced with permission from (Stewart et al. 2010)
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Fig1: Fluorescence intensities are shown as a function of time during the chase phase of two single-nucleotide turnover experiments in permeable rabbit fast-twitch muscle fibers. The fluorescence decay occurring during a chase with ATP following an incubation with mantATP [2′-/3′-O-(N′-methylanthraniloyl)-ATP] is shown (red, open circles). The rise in fluorescence intensity occurring during the inverse experiment in which the fiber was first incubated with ATP followed by a chase with mantATP is also shown (blue, open squares). The composition of the incubation and chase phases are shown above, color-coded with the data. The fluorescence changes in two phases, a rapid phase which has a time constant of approximately 20 s followed by a slow phase with a time constant of 230 s. The slower phase is attributed to the slow release of nucleotides from a fraction of myosin heads, which are in a “super relaxed” state. Reproduced with permission from (Stewart et al. 2010)

Mentions: A highly inhibited state of myosin in skeletal muscle was first observed by measuring single nucleotide turnovers (Stewart et al. 2010). The ATP turnover rate in relaxed permeable rabbit psoas fibers was measured by first incubating the fibers in mantATP followed by a chase with ATP. The fiber was relaxed in both solutions. During the chase phase, the fluorescence intensity of the fiber decreased as the bound mant nucleotides were released and replaced by ATP (Fig. 1). There was a rapid decay in fluorescence intensity followed by a slow decay. A second experimental approach was to incubate the fiber first in ATP, followed by a chase with mantATP, also shown in Fig. 1. The intensity rose as ATP was released and replaced by mantATP. The change in fluorescence occurred in two phases that mirrored those of the first experiment, showing that the mantATP turnover rate was similar to the ATP turnover rate. The rapid phase, which has a time constant of approximately 20 s, comprises multiple factors, including the release of non-specifically bound nucleotides, the release of nucleotides by a fraction of the normally relaxed myosin heads, and the diffusion of released nucleotides out of the fibers, requiring approximately 10 s (Cooke and Pate 1985). The time constant for the second phase is much slower, 230 s, and as discussed below, it arises from the release of nucleotides by a second fraction of myosin heads with a very slow ATP turnover. Although the data described above were obtained from rabbit fast twitch psoas fibers, Stewart et. al. also showed that a similar SRX could be observed in slow twitch rabbit soleus fibers, with a slightly shorter time constant of 156 s (Stewart et al. 2010).Fig. 1


The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle.

Cooke R - Biophys Rev (2011)

Fluorescence intensities are shown as a function of time during the chase phase of two single-nucleotide turnover experiments in permeable rabbit fast-twitch muscle fibers. The fluorescence decay occurring during a chase with ATP following an incubation with mantATP [2′-/3′-O-(N′-methylanthraniloyl)-ATP] is shown (red, open circles). The rise in fluorescence intensity occurring during the inverse experiment in which the fiber was first incubated with ATP followed by a chase with mantATP is also shown (blue, open squares). The composition of the incubation and chase phases are shown above, color-coded with the data. The fluorescence changes in two phases, a rapid phase which has a time constant of approximately 20 s followed by a slow phase with a time constant of 230 s. The slower phase is attributed to the slow release of nucleotides from a fraction of myosin heads, which are in a “super relaxed” state. Reproduced with permission from (Stewart et al. 2010)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3064898&req=5

Fig1: Fluorescence intensities are shown as a function of time during the chase phase of two single-nucleotide turnover experiments in permeable rabbit fast-twitch muscle fibers. The fluorescence decay occurring during a chase with ATP following an incubation with mantATP [2′-/3′-O-(N′-methylanthraniloyl)-ATP] is shown (red, open circles). The rise in fluorescence intensity occurring during the inverse experiment in which the fiber was first incubated with ATP followed by a chase with mantATP is also shown (blue, open squares). The composition of the incubation and chase phases are shown above, color-coded with the data. The fluorescence changes in two phases, a rapid phase which has a time constant of approximately 20 s followed by a slow phase with a time constant of 230 s. The slower phase is attributed to the slow release of nucleotides from a fraction of myosin heads, which are in a “super relaxed” state. Reproduced with permission from (Stewart et al. 2010)
Mentions: A highly inhibited state of myosin in skeletal muscle was first observed by measuring single nucleotide turnovers (Stewart et al. 2010). The ATP turnover rate in relaxed permeable rabbit psoas fibers was measured by first incubating the fibers in mantATP followed by a chase with ATP. The fiber was relaxed in both solutions. During the chase phase, the fluorescence intensity of the fiber decreased as the bound mant nucleotides were released and replaced by ATP (Fig. 1). There was a rapid decay in fluorescence intensity followed by a slow decay. A second experimental approach was to incubate the fiber first in ATP, followed by a chase with mantATP, also shown in Fig. 1. The intensity rose as ATP was released and replaced by mantATP. The change in fluorescence occurred in two phases that mirrored those of the first experiment, showing that the mantATP turnover rate was similar to the ATP turnover rate. The rapid phase, which has a time constant of approximately 20 s, comprises multiple factors, including the release of non-specifically bound nucleotides, the release of nucleotides by a fraction of the normally relaxed myosin heads, and the diffusion of released nucleotides out of the fibers, requiring approximately 10 s (Cooke and Pate 1985). The time constant for the second phase is much slower, 230 s, and as discussed below, it arises from the release of nucleotides by a second fraction of myosin heads with a very slow ATP turnover. Although the data described above were obtained from rabbit fast twitch psoas fibers, Stewart et. al. also showed that a similar SRX could be observed in slow twitch rabbit soleus fibers, with a slightly shorter time constant of 156 s (Stewart et al. 2010).Fig. 1

Bottom Line: Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle.In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding.Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry & Biophysics, Cardiovascular Research Institute, University of California, Box 2240, Genentech Hall, 600, 6th Street, San Francisco, CA 94158-2517 USA.

ABSTRACT
Resting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the "furnace" that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430-435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.

No MeSH data available.


Related in: MedlinePlus