Biology subjects

Sylow, L.

Publications and source records attributed to Sylow, L..

4 recordsLinked to original sources

bioRxiv2019

Housing temperature influences exercise training adaptations in mice

Exercise training is a powerful means to combat metabolic pathologies. Mice are extensively used to describe the benefits of exercise, but mild cold stress induced by housing temperatures may confound translation to humans. Thermoneutral housing is a strategy to make mice more metabolically similar to humans but its effects on exercise adaptations are unknown. Using voluntary wheel running, we show that thermoneutral housing blunted exercise-induced improvements in insulin action in muscle and adipose tissue. Moreover, thermoneutrality reduced the effects of training on energy expenditure, body composition, muscle and adipose tissue protein expressions, and the gut microbiome. The majority of these thermoneutral-dependent training adaptations could not be ascribed to a lower voluntary running volume. Thus, we conclude that organismal adaptations to exercise training in mice critically depend upon housing temperature. Our findings underscore the importance of housing temperature as an important parameter in the design and interpretation of murine exercise studies.\n\nHighlightsO_LIHousing at 30{degrees}C blunts several adaptations to exercise training in mice\nC_LIO_LIExercise-sensitive protein induction is dampened at 30{degrees}C in skeletal muscle\nC_LIO_LI30{degrees}C-housing blunts training-induced increase in insulin-stimulated glucose uptake\nC_LIO_LIGlucose tolerance is not improved by voluntary exercise training at 30{degrees}C housing\nC_LIO_LIDecreased running in 30{degrees}C housing is not due to overheating\nC_LI\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/651588v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (68K):\norg.highwire.dtl.DTLVardef@1e5b6acorg.highwire.dtl.DTLVardef@3be37corg.highwire.dtl.DTLVardef@1d3febborg.highwire.dtl.DTLVardef@f8da30_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG

physiology↗

bioRxiv2019

Mechanisms involved in follistatin-induced increased insulin action in skeletal muscle

BackgroundSkeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor {beta} (TGF-{beta}) superfamily, including activin A, which causes atrophy. TGF-{beta} superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined.\n\nMethodsTo elucidate if TGF-{beta} superfamily ligands regulate insulin action we used an adeno-associated virus gene editing approach to overexpress the activin A inhibitor, follistatin (Fst288) in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2 deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB).\n\nResultsFst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, p<0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, PDH-E1, and p70S6K (p<0.05). No correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake but Fst288 increased basal and insulin-stimulated protein synthesis. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced Activin A (-24%, p<0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.\n\nConclusionsWe here present evidence that Fst is a potent regulator of insulin action in muscle and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4 and PAK1 as Fst targets. A possible role for Fst in regulating glycemic control is suggested because circulating Fst more than doubled post RYGB surgery, a treatment that markedly improved insulin sensitivity. These findings demonstrate the therapeutic potential of inhibiting TGF-{beta} superfamily ligands to improve insulin action and Fsts relevance to muscle wasting associated insulin resistant conditions in mice and humans.

physiology↗

bioRxiv2019

The role of p-21 activated kinases (PAKs) in glucose homeostasis and skeletal muscle glucose uptake

ObjectiveSkeletal muscle glucose uptake is essential for maintaining whole-body glucose homeostasis and accounts for the majority of glucose disposal in response to insulin. The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle. Interestingly, PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle and PAK1 has been suggested to be required for insulin-stimulated GLUT4 translocation. However, the relative contribution of PAK1 and PAK2 to insulin-stimulated glucose uptake in mature skeletal muscle is unresolved. The aim of the present investigation was to determine the requirement for PAK1 and PAK2 in whole-body glucose homeostasis and insulin-stimulated glucose uptake in skeletal muscle. MethodsGlucose uptake was measured in isolated skeletal muscle incubated with a pharmacological inhibitor (IPA-3) of group I PAKs and in muscle from whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO and double whole-body PAK1 and muscle-specific PAK2 knockout mice. ResultsThe whole-body respiratory exchange ratio was largely unaffected by lack of PAK1 and/or PAK2. Whole-body glucose tolerance was mildly impaired in PAK2 mKO, but not PAK1 KO mice. IPA-3 partially reduced (-20%) insulin-stimulated glucose uptake in mouse soleus muscle. In contrast to a previous study of GLUT4 translocation in PAK1 KO mice, PAK1 KO muscles displayed normal insulin-stimulated glucose uptake in vivo and in isolated muscle. On the contrary, glucose uptake was slightly reduced in response to insulin in glycolytic extensor digitorum longus muscle lacking PAK2, alone (-18%) or in combination with PAK1 KO (-12%). ConclusionsInsulin-stimulated glucose uptake partly relies on PAK2, but not PAK1, in mouse skeletal muscle. Thus, the present study challenges that group I PAKs, and especially PAK1, are major regulators of whole-body glucose homeostasis and insulin-stimulated glucose uptake in skeletal muscle.

cell biology↗

bioRxiv2019

Exercise-stimulated muscle ROS production and glucose uptake requires NADPH oxidase 2

Reactive oxygen species (ROS) act as intracellular compartmentalized second messengers mediating metabolic stress-adaptation. In skeletal muscle fibers, ROS have been suggested to stimulate glucose transporter 4 (GLUT4)-dependent glucose transport during artificially evoked contraction ex vivo but whether myocellular ROS production is stimulated by in vivo exercise to control metabolism is unclear. Here, we combined exercise in humans and mice with fluorescent dyes, genetically-encoded biosensors, and NADPH oxidase 2 (NOX2) loss-of-function models to demonstrate that NOX2 is the main source of cytosolic ROS during moderate-intensity exercise in skeletal muscle. Furthermore, two NOX2 loss-of-function mouse models lacking either p47phox or Rac1 presented striking phenotypic similarities, including greatly reduced exercise-stimulated glucose uptake and GLUT4 translocation. These findings indicate that NOX2 is a major myocellular ROS source regulating glucose transport capacity during moderate-intensity exercise.

physiology↗