ORCID Profile
0000-0002-5259-5777
Current Organisation
ETH Zurich
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Publisher: The Endocrine Society
Date: 10-06-2016
DOI: 10.1210/EN.2016-1220
Abstract: Exercise has a potent insulin-sensitivity enhancing effect on skeletal muscle, but the intracellular mechanisms that mediate this effect are not well understood. In muscle, Ras-related C3 botulinum toxin substrate 1 (Rac1) regulates both insulin- and contraction-stimulated glucose transport and is dysregulated in insulin resistant muscle. However, whether Rac1 is involved in mediating enhanced insulin sensitivity after an acute bout of exercise is unresolved. To address this question, we investigated after exercise whole-body (insulin tolerance test) as well as muscle (insulin-stimulated 2-deoxyglucose transport in isolated soleus muscle) insulin sensitivity in inducible muscle-specific Rac1 knockout (mKO) and wild-type (WT) littermate mice. Previous exercise enhanced whole-body insulin sensitivity by 40% in WT mice and rescued the insulin intolerance in Rac1 mKO mice by improving whole-body insulin sensitivity by 230%. In agreement, previous exercise significantly improved insulin sensitivity by 20% in WT and by 40% in Rac1 mKO soleus muscles. These findings suggest that muscle Rac1 is dispensable for the insulin sensitizing effect of exercise. Moreover, insulin resistance in Rac1 mKO mice can be completely normalized by previous exercise explaining why insulin resistant patients can increase insulin action with exercise despite dysfunctional Rac1 activity in muscle.
Publisher: Wiley
Date: 22-02-2017
DOI: 10.1111/APHA.12851
Abstract: To determine whether repeated maximal-intensity hypoxic exercise induces larger beneficial adaptations on the hypoxia-inducible factor-1α pathway and its target genes than similar normoxic exercise, when combined with chronic hypoxic exposure. Lowland elite male team-sport athletes underwent 14 days of passive normobaric hypoxic exposure [≥14 h·day Hypoxia-inducible factor-1α subunit, vascular endothelial growth factor, myoglobin, peroxisome proliferator-activated receptor-gamma coactivator 1-α and mitochondrial transcription factor A mRNA levels increased at Post-1 (all P ≤ 0.05) in LHTLH, but not in LHTL or LLTL, and returned near baseline levels at Post-2. The protein expression of citrate synthase increased in LHTLH (P < 0.001 and P < 0.01 at Post-1 and Post-2, respectively) and LLTL (P < 0.01 and P < 0.05 at Post-1 and Post-2, respectively), whereas it decreased in LHTL at Post-1 and Post-2 (both P < 0.001). Combined with residence in normobaric hypoxia, repeated maximal-intensity hypoxic exercise induces short-term post-intervention beneficial changes in muscle transcriptional factors that are of larger magnitude (or not observed) than with similar normoxic exercise. The decay of molecular adaptations was relatively fast, with most of benefits already absent 3 weeks post-intervention.
Publisher: Informa UK Limited
Date: 03-2016
DOI: 10.2147/HP.S101133
Publisher: American Diabetes Association
Date: 07-04-2017
DOI: 10.2337/DB16-1138
Abstract: Exercise bypasses insulin resistance to increase glucose uptake in skeletal muscle and therefore represents an important alternative to stimulate glucose uptake in insulin-resistant muscle. Both Rac1 and AMPK have been shown to partly regulate contraction-stimulated muscle glucose uptake, but whether those two signaling pathways jointly account for the entire signal to glucose transport is unknown. We therefore studied the ability of contraction and exercise to stimulate glucose transport in isolated muscles with AMPK loss of function combined with either pharmacological inhibition or genetic deletion of Rac1. Muscle-specific knockout (mKO) of Rac1, a kinase-dead α2 AMPK (α2KD), and double knockout (KO) of β1 and β2 AMPK subunits (β1β2 KO) each partially decreased contraction-stimulated glucose transport in mouse soleus and extensor digitorum longus (EDL) muscle. Interestingly, when pharmacological Rac1 inhibition was combined with either AMPK β1β2 KO or α2KD, contraction-stimulated glucose transport was almost completely inhibited. Importantly, α2KD+Rac1 mKO double-transgenic mice also displayed severely impaired contraction-stimulated glucose transport, whereas exercise-stimulated glucose uptake in vivo was only partially reduced by Rac1 mKO with no additive effect of α2KD. It is concluded that Rac1 and AMPK together account for almost the entire ex vivo contraction response in muscle glucose transport, whereas only Rac1, but not α2 AMPK, regulates muscle glucose uptake during submaximal exercise in vivo.
No related grants have been discovered for Gommaar D'Hulst.