Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies

Activation of the PI3K–Akt–FoxO pathway induces cell growth, whereas its inhibition reduces cell survival and, in muscle, causes atrophy. Here, we report a novel mechanism that suppresses PI3K–Akt–FoxO signaling. Although skeletal muscle lacks desmosomes, it contains multiple desmosomal components, including plakoglobin. In normal muscle plakoglobin binds the insulin receptor and PI3K subunit p85 and promotes PI3K–Akt–FoxO signaling. During atrophy, however, its interaction with PI3K–p85 is reduced by the ubiquitin ligase Trim32 (tripartite motif containing protein 32). Inhibition of Trim32 enhanced plakoglobin binding to PI3K–p85 and promoted PI3K–Akt–FoxO signaling. Surprisingly, plakoglobin overexpression alone enhanced PI3K–Akt–FoxO signaling. Furthermore, Trim32 inhibition in normal muscle increased PI3K–Akt–FoxO signaling, enhanced glucose uptake, and induced fiber growth, whereas plakoglobin down-regulation reduced PI3K–Akt–FoxO signaling, decreased glucose uptake, and caused atrophy. Thus, by promoting plakoglobin–PI3K dissociation, Trim32 reduces PI3K–Akt–FoxO signaling in normal and atrophying muscle. This mechanism probably contributes to insulin resistance during fasting and catabolic diseases and perhaps to the myopathies and cardiomyopathies seen with Trim32 and plakoglobin mutations.

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β2-Adrenoceptor and insulin receptor expression in the skeletal muscle of streptozotocin induced diabetic rats: Antagonism by vitamin D3 and curcumin

European Journal of Pharmacology ◽

10.1016/j.ejphar.2012.02.050 ◽

2012 ◽

Vol 687 (1-3) ◽

pp. 14-20 ◽

Cited By ~ 17

Author(s):

Serene Xavier ◽

Jayanarayanan Sadanandan ◽

Naijil George ◽

Chiramadathikudiyil Skaria Paulose

Keyword(s):

Skeletal Muscle ◽

Insulin Receptor ◽

Vitamin D3 ◽

Diabetic Rats ◽

Receptor Expression ◽

Insulin Receptor Expression

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L-ARGININE SUPPLEMENTATION IMPROVES INSULIN RESISTANCE BY INCREASING THE INSULIN RECEPTOR EXPRESSION IN TYPE II DIABETIC RATS.

International Journal of Advanced Research ◽

10.21474/ijar01/9551 ◽

2019 ◽

Vol 7 (8) ◽

pp. 702-708

Author(s):

Nashwa ELKhazragy ◽

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Diabetic Rats ◽

Receptor Expression ◽

Type Ii ◽

Insulin Receptor Expression ◽

Arginine Supplementation

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Metabolic effects of prazosin on skeletal muscle insulin resistance in glucocorticoid-treated male rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00146.2016 ◽

2017 ◽

Vol 312 (1) ◽

pp. R62-R73 ◽

Cited By ~ 3

Author(s):

Emily C. Dunford ◽

Erin R. Mandel ◽

Sepideh Mohajeri ◽

Tara L. Haas ◽

Michael C. Riddell

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Protein Expression ◽

Muscle Atrophy ◽

Rodent Model ◽

Skeletal Muscle Atrophy ◽

Oral Glucose ◽

Capillary Rarefaction

High-dose glucocorticoids (GC) induce skeletal muscle atrophy, insulin resistance, and reduced muscle capillarization. Identification of treatments to prevent or reverse capillary rarefaction and metabolic deterioration caused by prolonged elevations in GCs would be therapeutically beneficial. Chronic administration of prazosin, an α1-adrenergic antagonist, increases skeletal muscle capillarization in healthy rodents and, recently, in a rodent model of elevated GCs and hyperglycemia. The purpose of this study was to determine whether prazosin administration would improve glucose tolerance and insulin sensitivity, through prazosin-mediated sparing of capillary rarefaction, in this rodent model of increased GC exposure. Prazosin was provided in drinking water (50 mg/l) to GC-treated or control rats (400 mg implants of either corticosterone or a wax pellet) for 7 or 14 days ( n = 5–14/group). Whole body measures of glucose metabolism were correlated with skeletal muscle capillarization (C:F) at 7 and 14 days in the four groups of rats. Individual C:F was found to be predictive of insulin sensitivity ( r2 = 0.4781), but not of glucose tolerance ( r2 = 0.1601) and compared with water only, prazosin treatment decreased insulin values during oral glucose challenge by approximately one-third in corticosterone (Cort)-treated animals. Cort treatment, regardless of duration, induced significant glycolytic skeletal muscle atrophy ( P < 0.05), decreased IRS-1 protein content ( P < 0.05), and caused elevations in FOXO1 protein expression ( P < 0.05), which were unaffected with prazosin administration. In summary, it appears that α1-adrenergic antagonism improves Cort-induced skeletal muscle vascular impairments and reduces insulin secretion during an oral glucose tolerance test, but is unable to improve the negative alterations directly affecting the myocyte, including muscle size and muscle signaling protein expression.

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