Regulation
of muscle
WILLIAM
carbohydrate
C. STANLEY”2
AND RICHARD
“Biodynarnic Laboratory, University University
of Rochester,
Rochester,
of Wisconsin, New
York 14642,
J.
metabolism
exercise
glucose
glycolysis
intermediary
metabo-
FROM A CONTROL THEORY standpoint is the overall goal achieved by the operation of several controls. Over the years a number of points of control have been identified in the pathways involved in muscle carbohydrate metabolism during exercise (Fig. 1). These points include: 1) the input of substrate at the top, either from blood glucose by a controlled transport process across the cell membrane or via breakdown of glycogen catalyzed by a well-controlled glycogen phosphorylase, 2) control of the rate of formation of triosephosphates by phosphofructokinase which is sensitive to a large number of metabolic intermediates, and 3) mass action effects in the section between triosephosphates and lactate. Although there is general agreement on the location of the controls in the pathways of muscle carbohydrate metabolism, uncertainty still exists concerning the precise nature of the control, and a precise understanding of the mechanisms of recruitment of these controls in response to muscular exercise is an ongoing problem. The regulation must involve integration of the glycolytic controls with other metabolic pathways, and the needs of the whole muscle in meeting the physiological demand. This review focuses on some aspects of current research toward understanding glycolytic control and its function during exercise. REGULATtON
SUBSTRATE
SUPPLY
TO
THE
Wisconsin
53706,
USA;
and tDepartmeni
of Physiology,
USA
This review examines the mechanisms that regulate muscle carbohydrate metabolism during exercise. Muscle carbohydrate utilization is regulated primarily by two factors, namely, delivery of substrate to the glycolytic pathway either from glycogenolysis or from transport of extracellular glucose into the fibers, and formation of triosephosphate by phosphofructokinase. The regulation involves the integration of the glycolytic controls with other metabolic controls and the needs of the whole muscle in meeting the physiological demand. The controls operating in the glycolytic sequence in vivo appear to couple glycolytic recruitment to signals from the rate of energy demand, the TCA cycle state, and the mitochondrial redox state so as to satisfy the major regulatory goal of maintaining the supply of ATP for tension development. Stanley, W. C.; Connett, R. J. Regulation of muscle carbohydrate metabolism during exercise. FASEB J. 5: 2155-2159; 1991. Words: lactate
exercise
CONNETTt
Madison,
ABSTRACT
Key lism
during
GLYCOLYTIC
PATHWAY As shown in Fig. 1, the inputs to glycolysis converge at glucose 6-phosphate (G6P).3 The first well-defined control points are those serving to generate G6P. This compound is generated from internal glycogen stores by the action of glycogen phosphorylase or is made from exogenous glucose.
The rate-limiting step for exogenous glucose use by contracting skeletal muscle is the controlled rate of glucose transport across the sarcolemmal membrane. Transport is a function of the abundance and activity of glucose transporters in the plasma membrane, and the transmembrane concentration gradient. As the intracellular glucose concentration is generally very low, the transmembrane gradient is dominated by the arterial glucose concentration. Arterial glucose homeostasis is maintained during exercise despite a 5- to 10-fold increase in the rate of muscle glucose uptake (1); in other words, glucose production, primarily by the liver from either glycogen stores or new synthesis, is regulated to match the increase in the rate of muscle glucose uptake. We will consider each process in turn. Glucose
delivery
Hepatic glucose production is controlled by: 1) the reciprocal stimulation/inhibition by hepatic portal venous levels of glucagon and insulin, 2) stimulation by catecholamines (epinephrine and norepinephrine), and 3) an increase in both release and the capacity to synthesize glucose by glucocorticoids, primarily cortisol. At rest the feedback signal for all of these mechanisms is a fall in plasma glucose concentration. In exercise, there is generally no decrease in blood glucose levels until after at least an hour of moderate to heavy work, yet the changes in the main controllers of hepatic glucose production, portal venous glucagon, and insulin levels occur early during exercise (2-4). The mechanism for the increase in glucagon secretion and decrease in insulin release during the early stages of exercise with euglycemia is unknown, although it might be directly driven by sympathetic stimulation of the pancreatic and a cells (5), a feed-forward control. Sympathetic stimulation of the pancreas results in a decrease in insulin release and stimulation of glucagon output (5); however, evidence for the activation of this mechanism during exercise has not been given. Additional evidence for glucoregulatory feed-forward mechanisms during exercise comes from the moderate increase (10-30%) in plasma glucose levels sometimes seen with the onset of moderate to heavy exercise (1). Two known feedforward mechanisms are epinephrine release from the adrenal
medulla
during
‘From The American tion of Muscle Carbohydrate
the
early
Physiological Metabolism
74th Annual
Meeting
Experimental W. C. Stanley
Biology, Washington, and J. 0. Holloszy.
tTo whom
phase
Society Symposium during Exercise presented
of the Federation
all correspondence
of heavy
D.C.,
should
exercise,
Regulaat the
of American Societies for April 3, 1990. Chaired by be sent, at: Biodynamics
Laboratory, University of Wisconsin, 2000 Observatory Dr., Madison, WI 53706, USA. tAbbreviations: F6P, fructose 6-phosphate; G6P, glucose 6-phosphate; GLUT1, erythrocyte glucose transporter; GLUT4, muscle/ adipose insulin responsive glucose transporter; PFK, phosphofructokinase; TCA, tricarboxylic acid.
2155 0892-6638/91/0005-2 155/$01.50.© FASEB www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on October 22, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
4,
Glycogen
G1P,’\+,I
S tp.1F’ (.
i...
.ir
Douen et al. (9) recently observed that both exercise and insulin caused an increase in the concentration of GLUT-4 transporter in the plasma membrane. The GLUT-i isoform appeared only in low concentrations in the plasma membranes, and was unaffected by exercise. Thus glycolytic substrate delivery from extracellular sources in exercise appears to depend on the controlled concentration of GLUT-4 glucose transporters in the plasma membrane.
9
Glucose
1
__-r
F6P
Glycogen IFI.
ATP+Cr
.
breakdown
and the firing of sympathetic nerves innervating the liver and pancreatic islets. Epinephrine stimulation of hepatic glucose production appears to be of secondary importance in exercising humans (6). Recent in vivo experiments with denervated livers have demonstrated that neural input to the liver is not crucial in maintaining glucose homeostasis during exercise (2).
The rate of glycogen breakdown in working muscle is dependent on the activity of glycogen phosphorylase. This enzyme exists in two forms: phosphorylase a (active) and phosphorylase b (inactive in the absence of AMP). Activation is regulated by phosphorylase kinase, which is activated by Ca2 and high pH (Fig. 1) (14), and also by 13-adrenergic receptor stimulation through cyclic AMP activation of protein kinase (15). In addition to these controls, direct feedback inhibition by G6P can occur. This gives a set of controls that includes endocrine signals (/3-stimulation), muscle activation (Ca2 and pH), and other metabolic activity (AMP and G6P). Contractions activate phosphorylase, but it reverts back to the inactive form after a few minutes, with a concomitant decrease in the rate of glycogenolysis (16). Epinephrine reactivates the enzyme and stimulates glycogenolysis in contracting muscle; however, epinephrine also activates the enzyme to the same extent in resting muscle, but has little effect on glycogenolysis (17). The rate of net glycogen breakdown increases during sustained exercise as an exponential function of work rate (18). This presents a paradox: phosphorylase activity is near resting values, yet net glycogenolysis proceeds during exercise. However, one must keep in mind that the net rate of glycogenolysis is the difference between the rates of the phosphorylase and synthase reactions. Studies with radiolabeled glucose have shown that glycogen synthesis continues even under conditions of net glycogen breakdown during muscle contractions (10). Thus glycogen synthase deactivation may play a role in regulating net glycogenolysis. Alternatively, the rate of glycogenolysis may depend on the feedback from other metabolic systems (17).
Glucose
Relative
L!i’q11..
-
-
AMP
FDP
-P1
AlP
S
3PG
..,
Cl)
I
___
_____
.
Those
NAl)
NADH+H
ato
2vate
/ADP
Figure 1. The glycolytic pathway and its regulators. elaboration of the regulatory mechanisms.
See text for an
transport
Contraction of skeletal muscle causes an increase in the rate of glucose transport into muscle fibers. Indirect evidence has been provided to suggest that a contraction-induced rise in cytosolic Ca2 + is involved in the stimulation of glucose transport (7) (Fig. 1). Two glucose transporter isoforms are in skeletal
muscle;
lin regulatable levels of the human
the
primary
glucose GLUT-i
erythrocyte.
one
is the
GLUT-4,
transporter (8); there are isoform, which is abundant
Insulin
results
in
the
or insu-
also low in the
translocation
of
GLUT-4
from an intracellular storage site to the plasma membrane (9). Muscle contractions, like insulin, increase the maximal rate of transport without appreciably affecting the Michaelis constant (7, 10). Treadmill running in rats causes a threefold increase in the rate of hindlimb glucose uptake, and a doubling in the number of glucose transporters on the plasma membranes as measured with cytochalasin-B
binding
(11).
A similar
response
is seen
with
an
increase in workload in the isolated rat heart (12). Thus exercise not only stimulates the translocation of glucose transporters from an intracellular storage site to the plasma membrane, it also increases the activity of these transporters (13).
2156
Vol. 5
May
1991
contribution
of exogenous
glucose
and
glycogen
Glycogen stores are normally the main supplier of glycolytic substrate in working muscle during short-term exercise (
of muscle
WILLIAM
carbohydrate
C. STANLEY”2
AND RICHARD
“Biodynarnic Laboratory, University University
of Rochester,
Rochester,
of Wisconsin, New
York 14642,
J.
metabolism
exercise
glucose
glycolysis
intermediary
metabo-
FROM A CONTROL THEORY standpoint is the overall goal achieved by the operation of several controls. Over the years a number of points of control have been identified in the pathways involved in muscle carbohydrate metabolism during exercise (Fig. 1). These points include: 1) the input of substrate at the top, either from blood glucose by a controlled transport process across the cell membrane or via breakdown of glycogen catalyzed by a well-controlled glycogen phosphorylase, 2) control of the rate of formation of triosephosphates by phosphofructokinase which is sensitive to a large number of metabolic intermediates, and 3) mass action effects in the section between triosephosphates and lactate. Although there is general agreement on the location of the controls in the pathways of muscle carbohydrate metabolism, uncertainty still exists concerning the precise nature of the control, and a precise understanding of the mechanisms of recruitment of these controls in response to muscular exercise is an ongoing problem. The regulation must involve integration of the glycolytic controls with other metabolic pathways, and the needs of the whole muscle in meeting the physiological demand. This review focuses on some aspects of current research toward understanding glycolytic control and its function during exercise. REGULATtON
SUBSTRATE
SUPPLY
TO
THE
Wisconsin
53706,
USA;
and tDepartmeni
of Physiology,
USA
This review examines the mechanisms that regulate muscle carbohydrate metabolism during exercise. Muscle carbohydrate utilization is regulated primarily by two factors, namely, delivery of substrate to the glycolytic pathway either from glycogenolysis or from transport of extracellular glucose into the fibers, and formation of triosephosphate by phosphofructokinase. The regulation involves the integration of the glycolytic controls with other metabolic controls and the needs of the whole muscle in meeting the physiological demand. The controls operating in the glycolytic sequence in vivo appear to couple glycolytic recruitment to signals from the rate of energy demand, the TCA cycle state, and the mitochondrial redox state so as to satisfy the major regulatory goal of maintaining the supply of ATP for tension development. Stanley, W. C.; Connett, R. J. Regulation of muscle carbohydrate metabolism during exercise. FASEB J. 5: 2155-2159; 1991. Words: lactate
exercise
CONNETTt
Madison,
ABSTRACT
Key lism
during
GLYCOLYTIC
PATHWAY As shown in Fig. 1, the inputs to glycolysis converge at glucose 6-phosphate (G6P).3 The first well-defined control points are those serving to generate G6P. This compound is generated from internal glycogen stores by the action of glycogen phosphorylase or is made from exogenous glucose.
The rate-limiting step for exogenous glucose use by contracting skeletal muscle is the controlled rate of glucose transport across the sarcolemmal membrane. Transport is a function of the abundance and activity of glucose transporters in the plasma membrane, and the transmembrane concentration gradient. As the intracellular glucose concentration is generally very low, the transmembrane gradient is dominated by the arterial glucose concentration. Arterial glucose homeostasis is maintained during exercise despite a 5- to 10-fold increase in the rate of muscle glucose uptake (1); in other words, glucose production, primarily by the liver from either glycogen stores or new synthesis, is regulated to match the increase in the rate of muscle glucose uptake. We will consider each process in turn. Glucose
delivery
Hepatic glucose production is controlled by: 1) the reciprocal stimulation/inhibition by hepatic portal venous levels of glucagon and insulin, 2) stimulation by catecholamines (epinephrine and norepinephrine), and 3) an increase in both release and the capacity to synthesize glucose by glucocorticoids, primarily cortisol. At rest the feedback signal for all of these mechanisms is a fall in plasma glucose concentration. In exercise, there is generally no decrease in blood glucose levels until after at least an hour of moderate to heavy work, yet the changes in the main controllers of hepatic glucose production, portal venous glucagon, and insulin levels occur early during exercise (2-4). The mechanism for the increase in glucagon secretion and decrease in insulin release during the early stages of exercise with euglycemia is unknown, although it might be directly driven by sympathetic stimulation of the pancreatic and a cells (5), a feed-forward control. Sympathetic stimulation of the pancreas results in a decrease in insulin release and stimulation of glucagon output (5); however, evidence for the activation of this mechanism during exercise has not been given. Additional evidence for glucoregulatory feed-forward mechanisms during exercise comes from the moderate increase (10-30%) in plasma glucose levels sometimes seen with the onset of moderate to heavy exercise (1). Two known feedforward mechanisms are epinephrine release from the adrenal
medulla
during
‘From The American tion of Muscle Carbohydrate
the
early
Physiological Metabolism
74th Annual
Meeting
Experimental W. C. Stanley
Biology, Washington, and J. 0. Holloszy.
tTo whom
phase
Society Symposium during Exercise presented
of the Federation
all correspondence
of heavy
D.C.,
should
exercise,
Regulaat the
of American Societies for April 3, 1990. Chaired by be sent, at: Biodynamics
Laboratory, University of Wisconsin, 2000 Observatory Dr., Madison, WI 53706, USA. tAbbreviations: F6P, fructose 6-phosphate; G6P, glucose 6-phosphate; GLUT1, erythrocyte glucose transporter; GLUT4, muscle/ adipose insulin responsive glucose transporter; PFK, phosphofructokinase; TCA, tricarboxylic acid.
2155 0892-6638/91/0005-2 155/$01.50.© FASEB www.fasebj.org by Univ Louisiana Dupre Library/Serials Dept (130.70.8.131) on October 22, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber
4,
Glycogen
G1P,’\+,I
S tp.1F’ (.
i...
.ir
Douen et al. (9) recently observed that both exercise and insulin caused an increase in the concentration of GLUT-4 transporter in the plasma membrane. The GLUT-i isoform appeared only in low concentrations in the plasma membranes, and was unaffected by exercise. Thus glycolytic substrate delivery from extracellular sources in exercise appears to depend on the controlled concentration of GLUT-4 glucose transporters in the plasma membrane.
9
Glucose
1
__-r
F6P
Glycogen IFI.
ATP+Cr
.
breakdown
and the firing of sympathetic nerves innervating the liver and pancreatic islets. Epinephrine stimulation of hepatic glucose production appears to be of secondary importance in exercising humans (6). Recent in vivo experiments with denervated livers have demonstrated that neural input to the liver is not crucial in maintaining glucose homeostasis during exercise (2).
The rate of glycogen breakdown in working muscle is dependent on the activity of glycogen phosphorylase. This enzyme exists in two forms: phosphorylase a (active) and phosphorylase b (inactive in the absence of AMP). Activation is regulated by phosphorylase kinase, which is activated by Ca2 and high pH (Fig. 1) (14), and also by 13-adrenergic receptor stimulation through cyclic AMP activation of protein kinase (15). In addition to these controls, direct feedback inhibition by G6P can occur. This gives a set of controls that includes endocrine signals (/3-stimulation), muscle activation (Ca2 and pH), and other metabolic activity (AMP and G6P). Contractions activate phosphorylase, but it reverts back to the inactive form after a few minutes, with a concomitant decrease in the rate of glycogenolysis (16). Epinephrine reactivates the enzyme and stimulates glycogenolysis in contracting muscle; however, epinephrine also activates the enzyme to the same extent in resting muscle, but has little effect on glycogenolysis (17). The rate of net glycogen breakdown increases during sustained exercise as an exponential function of work rate (18). This presents a paradox: phosphorylase activity is near resting values, yet net glycogenolysis proceeds during exercise. However, one must keep in mind that the net rate of glycogenolysis is the difference between the rates of the phosphorylase and synthase reactions. Studies with radiolabeled glucose have shown that glycogen synthesis continues even under conditions of net glycogen breakdown during muscle contractions (10). Thus glycogen synthase deactivation may play a role in regulating net glycogenolysis. Alternatively, the rate of glycogenolysis may depend on the feedback from other metabolic systems (17).
Glucose
Relative
L!i’q11..
-
-
AMP
FDP
-P1
AlP
S
3PG
..,
Cl)
I
___
_____
.
Those
NAl)
NADH+H
ato
2vate
/ADP
Figure 1. The glycolytic pathway and its regulators. elaboration of the regulatory mechanisms.
See text for an
transport
Contraction of skeletal muscle causes an increase in the rate of glucose transport into muscle fibers. Indirect evidence has been provided to suggest that a contraction-induced rise in cytosolic Ca2 + is involved in the stimulation of glucose transport (7) (Fig. 1). Two glucose transporter isoforms are in skeletal
muscle;
lin regulatable levels of the human
the
primary
glucose GLUT-i
erythrocyte.
one
is the
GLUT-4,
transporter (8); there are isoform, which is abundant
Insulin
results
in
the
or insu-
also low in the
translocation
of
GLUT-4
from an intracellular storage site to the plasma membrane (9). Muscle contractions, like insulin, increase the maximal rate of transport without appreciably affecting the Michaelis constant (7, 10). Treadmill running in rats causes a threefold increase in the rate of hindlimb glucose uptake, and a doubling in the number of glucose transporters on the plasma membranes as measured with cytochalasin-B
binding
(11).
A similar
response
is seen
with
an
increase in workload in the isolated rat heart (12). Thus exercise not only stimulates the translocation of glucose transporters from an intracellular storage site to the plasma membrane, it also increases the activity of these transporters (13).
2156
Vol. 5
May
1991
contribution
of exogenous
glucose
and
glycogen
Glycogen stores are normally the main supplier of glycolytic substrate in working muscle during short-term exercise (
