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Programmed cell death 5 improves skeletal muscle insulin resistance by inhibiting IRS-1 ubiquitination through
Bo Li1, Jingjing Ye2, Ruxia Liu1
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China.
Aims:
Insulin resistance is defined as the decreased sensitivity of tissues and organs to insulin and it is the main pathological basis of metabolic syndrome. PDCD5 is widely expressed in tissues including skeletal muscle and liver, but its exact function and the role in insulin resistance has not been studied. The present study is to explore the effect of PDCD5 on insulin resistance in skeletal muscle, the largest target organ of insulin, and its mechanism.
Materials And Methods:
Mice were fed with high-fat diet to establish obesity model. C2C12 myoblasts differentiated into myotubes and then were treated with palmitate to induce insulin resistance. Gain-of-function and loss-of-function experiments were performed by infecting C2C12 with adenovirus containing PDCD5 cDNA or PDCD5 shRNA.
Key Findings:
PDCD5 protein was first increased and then decreased in the skeletal muscle from high-fat diet induced obese mice and consistently in palmitate induced insulin resistance C2C12 myotubes. Overexpression of PDCD5 in C2C12 cells did not affect the sensitivity to insulin but inhibited the palmitate induced insulin resistance, while knockdown of PDCD5 aggravated the insulin resistance. Mechanistically, PDCD5 interacted with ubiquitin ligase MDM2; overexpression of PDCD5 decreased MDM2 protein level, inhibited the increased interaction of MDM2 with IRS-1 and the degradation of IRS-1 by palmitate stimulation.
Significance:
PDCD5 is upregulated during the early stage of insulin resistance in skeletal muscle. The increased PDCD5 inhibits IRS-1 ubiquitination, increases the stability of IRS-1 by interacting with and degrading MDM2, thus providing a protective effect on insulin resistance in skeletal muscle.
Insights
Programmed cell death 5 (PDCD5) protects against skeletal muscle insulin resistance by stabilizing IRS-1. Upregulated PDCD5 early in insulin resistance prevents IRS-1 degradation, offering a therapeutic target for metabolic syndrome.
Area of Science:
- Molecular Biology
- Metabolic Diseases
- Cellular Signaling
Background:
- Insulin resistance, a hallmark of metabolic syndrome, involves decreased tissue sensitivity to insulin.
- The role of Programmed cell death 5 (PDCD5) in insulin resistance, particularly in skeletal muscle, remains largely uncharacterized.
- Skeletal muscle is a primary insulin target organ, making its response to insulin crucial for metabolic homeostasis.
Purpose of the Study:
- To investigate the function of PDCD5 in skeletal muscle insulin resistance.
- To elucidate the underlying molecular mechanisms by which PDCD5 influences insulin signaling pathways.
Main Methods:
- High-fat diet-induced obesity model in mice.
- Palmitate treatment of C2C12 myotubes to mimic insulin resistance.
- Gain-of-function and loss-of-function studies using PDCD5 overexpression and knockdown in C2C12 cells.
Main Results:
- PDCD5 levels initially increase then decrease in skeletal muscle of obese mice and insulin-resistant myotubes.
- PDCD5 overexpression protected against palmitate-induced insulin resistance; PDCD5 knockdown exacerbated it.
- PDCD5 interacts with MDM2, reducing MDM2 levels and inhibiting palmitate-induced IRS-1 ubiquitination and degradation.
Conclusions:
- PDCD5 is upregulated early in skeletal muscle insulin resistance.
- PDCD5 enhances insulin sensitivity by interacting with MDM2, thereby stabilizing IRS-1.
- PDCD5 exhibits a protective role against insulin resistance in skeletal muscle.
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