JNK1 deficiency does not enhance muscle glucose metabolism in lean mice

Witczak, Carol A.; Hirshman, Michael F.; Jessen, Niels; Fujii, Nobuharu; Seifert, Matthew; Brandauer, Josef; Hotamışlıgil, Gökhan S.; Goodyear, Laurie J.

doi:10.1016/j.bbrc.2006.09.158

Cited by 20 publications

(14 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acute exercise effects on glucose transport and glycogen synthesis are probably not mediated by ERK1/2, as inhibitors of MAPK/ERK kinase abolish contraction-stimulated ERK1/2 phosphorylation without affecting glucose transport (31,90). Additional studies show that JNK does not regulate contraction-stimulated glucose transport or glycogen metabolism in skeletal muscle (25,89).…”

Section: Metabolic Actions Of Mapk Activationmentioning

confidence: 92%

Exercise, MAPK, and NF-κB signaling in skeletal muscle

Kramer¹,

Goodyear²

2007

Journal of Applied Physiology

319

301

View full text Add to dashboard Cite

Mitogen-activated protein kinases (MAPKs) and NF-kappaB are two major regulators of gene transcription and metabolism in response to oxidative, energetic, and mechanical stress in skeletal muscle. Chronic activation of these signaling pathways has been implicated in the development and perpetuation of various pathologies, such as diabetes and cachexia. However, both MAPK and NF-kappaB are also stimulated by exercise, which promotes improvements in fuel homeostasis and can prevent skeletal muscle atrophy. This review will first discuss the major MAPK signaling modules in skeletal muscle, their differential activation by exercise, and speculated functions on acute substrate metabolism and exercise-induced gene expression. Focus will then shift to examination of the NF-kappaB pathway, including its mechanism of activation by cellular stress and its putative mediation of exercise-stimulated adaptations in antioxidant status, tissue regeneration, and metabolism. Although limited, there is additional evidence to suggest cross talk between MAPK and NF-kappaB signals with exercise. The objectives herein are twofold: 1) to determine how and why exercise activates MAPK and NF-kappaB; and 2) to resolve their paradoxical activation during diseased and healthy conditions.

show abstract

Section: Metabolic Actions Of Mapk Activationmentioning

confidence: 92%

Exercise, MAPK, and NF-κB signaling in skeletal muscle

Kramer¹,

Goodyear²

2007

Journal of Applied Physiology

319

301

View full text Add to dashboard Cite

show abstract

“…Prior to labeled glucose, a baseline blood sample was taken to assess fasting blood glucose and background radioactivity levels. 3 H]2DG were determined as described previously (Ferre et al 1985, Witczak et al 2006. Briefly, frozen tissue was homogenized in ice-cold buffer containing 20 mM Tris-HCl, 5 mM EDTA, 10 mM Na 4 P 2 O 7 , 100 mM NaF, 2 mM NaVO 4 , 0.01 mM leupeptin, 3 mM benzamidine, 1 mM phenylmethylsulfonyl fluoride, and 10 mg/ml aprotinin.…”

Section: Muscle Glucose Uptake In Vivomentioning

confidence: 99%

IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer

Dool¹,

Mashhedi²,

Zakikhani³

et al. 2011

Endocrine-Related Cancer

View full text Add to dashboard Cite

Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin responsive, but it is unclear whether safe and effective therapies that target the insulin receptor (IR), which is homologous to oncogenes of the tyrosine kinase class, can be developed. We demonstrate that both pharmacologic inhibition of IR family tyrosine kinase activity and insulin deficiency have antineoplastic activity in a model of insulin-responsive breast cancer. Unexpectedly, in contrast to insulin deficiency, pharmacologic IR family inhibition does not lead to significant hyperglycemia and is well tolerated. We show that pharmacokinetic factors explain the tolerability of receptor inhibition relative to insulin deficiency, as the small molecule receptor kinase inhibitor BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers insulin levels only in settings of hyperinsulinemia, had minimal activity in this normoinsulinemic model. These findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors and suggest that therapeutic targeting of the IR family for cancer treatment is practical.

show abstract

“…Skeletal muscle glucose uptake and glycogen synthesis in vivo were measured as previously described (12,29). Briefly, mice were fasted overnight and then anesthetized with pentobarbital sodium.…”

Section: Preparation Of Muscle Tissue Lysatesmentioning

confidence: 99%

Insulin promotes glycogen synthesis in the absence of GSK3 phosphorylation in skeletal muscle

Bouskila¹,

Hirshman²,

Jensen³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Insulin promotes dephosphorylation and activation of glycogen synthase (GS) by inactivating glycogen synthase kinase (GSK) 3 through phosphorylation. Insulin also promotes glucose uptake and glucose 6-phosphate (G-6- P) production, which allosterically activates GS. The relative importance of these two regulatory mechanisms in the activation of GS in vivo is unknown. The aim of this study was to investigate if dephosphorylation of GS mediated via GSK3 is required for normal glycogen synthesis in skeletal muscle with insulin. We employed GSK3 knockin mice in which wild-type GSK3α and -β genes are replaced with mutant forms (GSK3α/βS21A/S21A/S9A/S9A), which are nonresponsive to insulin. Although insulin failed to promote dephosphorylation and activation of GS in GSK3α/βS21A/S21A/S9A/S9Amice, glycogen content in different muscles from these mice was similar compared with wild-type mice. Basal and epinephrine-stimulated activity of muscle glycogen phosphorylase was comparable between wild-type and GSK3 knockin mice. Incubation of isolated soleus muscle in Krebs buffer containing 5.5 mM glucose in the presence or absence of insulin revealed that the levels of G-6- P, the rate of [14C]glucose incorporation into glycogen, and an increase in total glycogen content were similar between wild-type and GSK3 knockin mice. Injection of glucose containing 2-deoxy-[3H]glucose and [14C]glucose also resulted in similar rates of muscle glucose uptake and glycogen synthesis in vivo between wild-type and GSK3 knockin mice. These results suggest that insulin-mediated inhibition of GSK3 is not a rate-limiting step in muscle glycogen synthesis in mice. This suggests that allosteric regulation of GS by G-6- P may play a key role in insulin-stimulated muscle glycogen synthesis in vivo.

show abstract

JNK1 deficiency does not enhance muscle glucose metabolism in lean mice

Cited by 20 publications

References 30 publications

Exercise, MAPK, and NF-κB signaling in skeletal muscle

Exercise, MAPK, and NF-κB signaling in skeletal muscle

IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer

Insulin promotes glycogen synthesis in the absence of GSK3 phosphorylation in skeletal muscle

Contact Info

Product

Resources

About