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- Al-Khalili, L, et al.
(författare)
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Proteasome inhibition in skeletal muscle cells unmasks metabolic derangements in type 2 diabetes
- 2014
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Ingår i: American journal of physiology. Cell physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 307:9, s. C774-C787
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Tidskriftsartikel (refereegranskat)abstract
- Two-dimensional difference gel electrophoresis (2-D DIGE)-based proteome analysis has revealed intrinsic insulin resistance in myotubes derived from type 2 diabetic patients. Using 2-D DIGE-based proteome analysis, we identified a subset of insulin-resistant proteins involved in protein turnover in skeletal muscle of type 2 diabetic patients, suggesting aberrant regulation of the protein homeostasis maintenance system underlying metabolic disease. We then validated the role of the ubiquitin-proteasome system (UPS) in myotubes to investigate whether impaired proteasome function may lead to metabolic arrest or insulin resistance. Myotubes derived from muscle biopsies obtained from people with normal glucose tolerance (NGT) or type 2 diabetes were exposed to the proteasome inhibitor bortezomib (BZ; Velcade) without or with insulin. BZ exposure increased protein carbonylation and lactate production yet impaired protein synthesis and UPS function in myotubes from type 2 diabetic patients, marking the existence of an insulin-resistant signature that was retained in cultured myotubes. In conclusion, BZ treatment further exacerbates insulin resistance and unmasks intrinsic features of metabolic disease in myotubes derived from type 2 diabetic patients. Our results highlight the existence of a confounding inherent abnormality in cellular protein dynamics in metabolic disease, which is uncovered through concurrent inhibition of the proteasome system.
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| 4. |
- Jiang, LQ, et al.
(författare)
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Constitutively active calcineurin in skeletal muscle increases endurance performance and mitochondrial respiratory capacity
- 2010
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 298:1, s. E8-E16
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Tidskriftsartikel (refereegranskat)abstract
- Expression of an activated form of calcineurin in skeletal muscle selectively up-regulates slow-fiber-specific gene expression. Here, we tested the hypothesis that expression of activated calcineurin in skeletal muscle influences body composition, energy homeostasis, and exercise performance. Using transgenic mice expressing activated calcineurin (CnA*) in skeletal muscle (MCK-CnA* transgenic mice), we determined whether skeletal muscle reprogramming by calcineurin activation affects exercise performance and skeletal muscle mitochondrial function. Body weight and extensor digitorum longus (EDL) skeletal muscle weight were reduced 10% in MCK-CnA* mice compared with wild-type littermates. Basal oxygen consumption, food intake, and voluntary exercise behavior were unchanged between MCK-CnA* and wild-type mice. However, when total energy expenditure was normalized by fat-free mass, energy expenditure was increased in MCK-CnA* mice. An endurance performance treadmill running test revealed MCK-CnA* mice are fatigue resistant and run 50% farther before exhaustion. After a standardized exercise bout, glycogen and triglyceride content in EDL muscle was higher in MCK-CnA* vs. wild-type mice. Mitochondrial respiratory capacity was increased 35% in EDL muscle from resting MCK-CnA* mice. In conclusion, our results provide evidence to support the hypothesis that calcineurin activation in skeletal muscle increases mitochondrial oxidative function and energy substrate storage, which contributes to enhanced endurance exercise performance. These adaptive changes occur as a consequence of a lifelong expression of a constitutively active calcineurin and mimic the response to chronic endurance training.
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