Onslev, J. | Search bioRxiv

bioRxiv2023

Reducing the mitochondrial oxidative burden alleviates lipid-induced insulin resistance in human skeletal muscle

Pre-clinical models suggest a causative nexus between mitochondrial oxidative stress and insulin resistance. However, the translational and pathophysiological significance of this mechanism in humans remains unclear. Herein, we employed an invasive in vivo mechanistic approach in humans to manipulate mitochondrial redox state while assessing insulin action. To this end, we combined intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mtAO) in conjunction with insulin clamp studies. During lipid overload, insulin-stimulated muscle glucose uptake, as determined by the femoral arteriovenous balance technique, was increased by mtAO. At the muscle molecular level, mtAO did not affect canonical insulin signaling but augmented insulin-stimulated GLUT4 translocation while decreasing the mitochondrial oxidative burden under lipid oversupply. Ex vivo studies revealed that mtAO ameliorated features of mitochondrial bioenergetics, including diminished mitochondrial H2O2 emission, in muscle fibers exposed to high intracellular lipid levels. These findings provide translational and mechanistic evidence implicating mitochondrial oxidants in the development of lipid-induced muscle insulin resistance in humans. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/535538v2_ufig1.gif" ALT="Figure 1"> View larger version (86K): org.highwire.dtl.DTLVardef@157d44eorg.highwire.dtl.DTLVardef@13358dborg.highwire.dtl.DTLVardef@e958eorg.highwire.dtl.DTLVardef@17cbc6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Beta2-adrenoceptor agonist salbutamol increases leg glucose uptake and metabolic rate but not muscle glycogen resynthesis in recovery from resistance exercise of the quadriceps in lean young men

ContentBeta2-agonists evoke potent acute increases in peripheral glucose uptake and energy expenditure at rest. Exercise has been shown to blunt these effects. Whether this attenuation is extended into recovery from exercise is unknown. ObjectiveTo examine the effect of beta2-agonists on leg glucose uptake and leg metabolic rate in recovery from exercise. DesignIn a randomized, placebo-controlled, cross-over study using arteriovenous balance technique and analysis of thigh muscle biopsies we investigated the effect of 24mg oral salbutamol (a selective beta2-agonist) on leg glucose, oxygen, and lactate at rest, during exercise, and in recovery, as well as on muscle glycogen resynthesis. ParticipantsHealthy, lean, young men (n=12). ResultsLeg glucose uptake tended to be two-fold higher at rest (0.22{+/-}0.12mmol/min, P=0.06). Accumulated leg glucose uptake was higher in recovery (21.1{+/-}6mmol, P=0.018) with salbutamol, but not during exercise. Leg oxygen uptake was 80% greater at rest (11{+/-}2.1mmol/min, P<0.01). Accumulated leg oxygen uptake was higher in recovery (1755{+/-}348mL, P<0.01) with salbutamol, but not during exercise. Muscle glycogen was lower with salbutamol 0.5h (109{+/-}25mmol/mg dry-weight, P<0.01) and 5h (101{+/-}19mmol/mg dry-weight, P<0.01) into recovery, suggestive of augmented glycogen utilization during exercise. There was no difference in glycogen resynthesis or glycogen synthase activity in the 5-hour recovery period with salbutamol. ConclusionsThese findings suggest that while resistance exercise confounds the augmentation of leg glucose uptake and metabolic rate induced by beta2-agonist at rest, this suppression is not conserved into recovery from exercise.

physiology↗