Enhanced Local Skeletal Muscle Oxidative Capacity and Microvascular Blood Flow Following 7-Day Ischemic Preconditioning in Healthy Humans

There is considerable support for the concept that insulin-mediated increases in microvascular blood flow to muscle impact significantly on muscle glucose uptake. Since the microvascular blood flow increases with insulin have been shown to be nitric oxide-dependent inhibition of cGMP-degrading phosphodiesterases (cGMP PDEs) is predicted to enhance insulin-mediated increases in microvascular perfusion and muscle glucose uptake. Therefore, we studied the effects of the pan-cGMP PDE inhibitor zaprinast on the metabolic and vascular actions of insulin in muscle. Hyperinsulinemic euglycemic clamps (3 mU·min−1·kg−1) were performed in anesthetized rats and changes in microvascular blood flow assessed from rates of 1-methylxanthine metabolism across the muscle bed by capillary xanthine oxidase in response to insulin and zaprinast. We also characterized cGMP PDE isoform expression in muscle by real-time PCR and immunostaining of frozen muscle sections. Zaprinast enhanced insulin-mediated microvascular perfusion by 29% and muscle glucose uptake by 89%, while whole body glucose infusion rate during insulin infusion was increased by 33% at 2 h. PDE2, -9, and -10 were the major isoforms expressed at the mRNA level in muscle, while PDE1B, -9A, -10A, and -11A proteins were expressed in blood vessels. Acute administration of the cGMP PDE inhibitor zaprinast enhances muscle microvascular blood flow and glucose uptake response to insulin. The expression of a number of cGMP PDE isoforms in skeletal muscle suggests that targeting specific cGMP PDE isoforms may provide a promising avenue for development of a novel class of therapeutics for enhancing muscle insulin sensitivity.

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Regulation of Skeletal Muscle Oxidative Capacity and Insulin Signaling by the Mitochondrial Rhomboid Protease PARL

Cell Metabolism ◽

10.1016/j.cmet.2010.04.004 ◽

2010 ◽

Vol 11 (5) ◽

pp. 412-426 ◽

Cited By ~ 52

Author(s):

Anthony E. Civitarese ◽

Paul S. MacLean ◽

Stacy Carling ◽

Lyndal Kerr-Bayles ◽

Ryan P. McMillan ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Signaling ◽

Oxidative Capacity ◽

Rhomboid Protease ◽

Muscle Oxidative Capacity

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Acute, local infusion of angiotensin II impairs microvascular and metabolic insulin sensitivity in skeletal muscle

Cardiovascular Research ◽

10.1093/cvr/cvy225 ◽

2018 ◽

Vol 115 (3) ◽

pp. 590-601 ◽

Cited By ~ 4

Author(s):

Dino Premilovac ◽

Emily Attrill ◽

Stephen Rattigan ◽

Stephen M Richards ◽

Jeonga Kim ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Skeletal Muscle ◽

Heart Rate ◽

Blood Flow ◽

Glucose Uptake ◽

Microvascular Blood Flow ◽

Euglycaemic Clamp ◽

Hyperinsulinaemic Euglycaemic Clamp ◽

Skeletal Muscle Glucose Uptake

Abstract Aims Angiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin’s microvascular and metabolic actions in skeletal muscle. Methods and results Adult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic clamp), or insulin (hyperinsulinaemic euglycaemic clamp) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic clamp) infusion. In all animals’ systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic clamp inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin’s effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake. Conclusions Acute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin’s microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects.

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Blood flow to different skeletal muscle fiber types during contraction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1983.245.2.h265 ◽

1983 ◽

Vol 245 (2) ◽

pp. H265-H275 ◽

Cited By ~ 30

Author(s):

B. G. Mackie ◽

R. L. Terjung

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Muscle Fiber ◽

Fiber Type ◽

Oxidative Capacity ◽

Skeletal Muscle Fiber ◽

Muscle Fiber Types ◽

Fiber Types ◽

Blood Flows ◽

Fast Twitch

Blood flow to fast-twitch red (FTR), fast-twitch white (FTW), and slow-twitch red (STR) muscle fiber sections of the gastrocnemius-plantaris-soleus muscle group was determined using 15 +/- 3-microns microspheres during in situ stimulation in pentobarbital-anesthetized rats. Steady-state blood flows were assessed during the 10th min of contraction using twitch (0.1, 0.5, 1, 3, and 5 Hz) and tetanic (7.5, 15, 30, 60, and 120/min) stimulation conditions. In addition, an earlier blood flow determination was begun at 3 min (twitch series) or at 30 s (tetanic series) of stimulation. Blood flow was highest in the FTR (220-240 ml X min-1 X 100 g-1), intermediate in the STR (140), and lowest in the FTW (70-80) section during tetanic contraction conditions estimated to coincide with the peak aerobic function of each fiber type. These blood flows are fairly proportional to the differences in oxidative capacity among fiber types. Further, their absolute values are similar to those predicted from the relationship between blood flow and oxidative capacity found by others for dog and cat muscles. During low-frequency contraction conditions, initial blood flow to the FTR and STR sections were excessively high and not dependent on contraction frequency. However, blood flows subsequently decreased to values in keeping with the relative energy demands. In contrast, FTW muscle did not exhibit this time-dependent relative hyperemia. Thus, besides the obvious quantitative differences between skeletal muscle fiber types, there are qualitative differences in blood flow response during contractions. Our findings establish that, based on fiber type composition, a heterogeneity in blood flow distribution can occur within a whole muscle during contraction.

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