Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans.

Preclinical models suggest mitochondria-derived oxidative stress as an underlying cause of insulin resistance. However, it remains unknown whether this pathophysiological mechanism is conserved in humans. Here, we used an invasive in vivo mechanistic approach to interrogate muscle insulin action while selectively manipulating the mitochondrial redox state in humans.

Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species.

Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear.

Microtubule-mediated GLUT4 trafficking is disrupted in insulin-resistant skeletal muscle.

Microtubules serve as tracks for long-range intracellular trafficking of glucose transporter 4 (GLUT4), but the role of this process in skeletal muscle and insulin resistance is unclear. Here, we used fixed and live-cell imaging to study microtubule-based GLUT4 trafficking in human and mouse muscle fibers and L6 rat muscle cells. We found GLUT4 localized on the microtubules in mouse and human muscle fibers.

Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle.

In mice, exercise is suggested to activate the mechanistic target of rapamycin complex 2 (mTORC2) in skeletal muscle, and mTORC2 is required for normal muscle glucose uptake during exercise. Whether this translates to human skeletal muscle and what signaling pathways facilitate the exercise-induced mTORC2 activation is unknown. We herein tested the hypothesis that exercise increases mTORC2 activity in human skeletal muscle and investigated if β-adrenergic receptor (AR) activation mediates exercise-induced mTORC2 activation.

AXIN1 knockout does not alter AMPK/mTORC1 regulation and glucose metabolism in mouse skeletal muscle.

Key Points: Tamoxifen-inducible skeletal muscle-specific AXIN1 knockout (AXIN1 imKO) in mouse does not affect whole-body energy substrate metabolism. AXIN1 imKO does not affect AICAR or insulin-stimulated glucose uptake in adult skeletal muscle. AXIN1 imKO does not affect adult skeletal muscle AMPK or mTORC1 signalling during AICAR/insulin/amino acid incubation, contraction and exercise.

Contraction-regulated mTORC1 and protein synthesis: Influence of AMPK and glycogen.

Key Points: AMP-activated protein kinase (AMPK)-dependent Raptor Ser792 phosphorylation does not influence mechanistic target of rapamycin complex 1 (mTORC1)-S6K1 activation by intense muscle contraction. α -AMPK activity-deficient mice have lower contraction-stimulated protein synthesis. Increasing glycogen activates mTORC1-S6K1.

The ULK1/2 and AMPK Inhibitor SBI-0206965 Blocks AICAR and Insulin-Stimulated Glucose Transport.

The small molecule kinase inhibitor SBI-0206965 was originally described as a specific inhibitor of ULK1/2. More recently, it was reported to effectively inhibit AMPK and several studies now report its use as an AMPK inhibitor. Currently, we investigated the specificity of SBI-0206965 in incubated mouse skeletal muscle, measuring the effect on analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated AMPK-dependent glucose transport and insulin-stimulated AMPK-independent glucose uptake.