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Published on: September 17, 2015
Short-chain fatty acid propionate alleviates Akt2 knockout-induced myocardial contractile dysfunction
Linlin Li1, Yinan Hua, Jun Ren
1Department of Pharmacology, Xinjiang Medical University, Urumqi, China.
Abstract:
BACKGROUND AND AIMS. Dysregulation of Akt has been implicated in diseases such as cancer and diabetes, although little is known about the role of Akt deficiency on cardiomyocyte contractile function. This study was designed to examine the effect of Akt2 knockout-induced cardiomyocyte contractile response and the effect of dietary supplementation of short-chain fatty acid propionate on Akt2 knockout-induced cardiac dysfunction, if any. METHODS AND RESULTS. Adult male wild-type (WT) and Akt2 knockout mice were treated with propionate (0.3 g/kg, p.o.) or vehicle for 7 days. Oral glucose tolerance test (OGTT) was performed. Cardiomyocyte contractile function and mitochondrial membrane potential were assessed. Expression of insulin-signaling molecules Akt, PTEN, GSK3β, and eNOS receptors for short-chain fatty acids GPR41, and GPR43 as well as protein phosphatase PP2AA, PP2AB, PP2C were evaluated using Western blot analysis. Our results revealed that Akt2 knockout led to overt glucose intolerance, compromised cardiomyocyte contractile function (reduced peak shortening and maximal velocity of shortening/relengthening as well as prolonged relengthening), loss of mitochondrial membrane potential, decreased GPR41 and elevated GPR43 expression, all of which, with the exception of glucose intolerance and elevated GPR43 level, were significantly attenuated by propionate. Neither Akt2 knockout nor propionate affected the expression of protein phosphatases, eNOS, pan, and phosphorylated PTEN and GSK3β. CONCLUSIONS. Taken together, these data depicted that Akt2 knockout may elicit cardiomyocyte contractile and mitochondrial defects and a beneficial role of propionate or short-chain fatty acids against Akt2 deficiency-induced cardiac anomalies.
Insights
Akt2 deficiency impairs heart function and glucose tolerance. Short-chain fatty acid propionate partially reversed these cardiac defects in mice, suggesting a therapeutic role.
Area of Science:
- Cardiology
- Molecular Biology
- Metabolic Diseases
Background:
- Akt signaling pathway dysregulation is linked to cancer and diabetes.
- The specific role of Akt deficiency in cardiomyocyte contractile function remains largely unknown.
- Akt2 knockout mice provide a model to study cardiac dysfunction.
Purpose of the Study:
- To investigate the impact of Akt2 deficiency on cardiomyocyte contractile function.
- To determine if propionate supplementation can mitigate Akt2 knockout-induced cardiac dysfunction.
- To explore the effects on glucose metabolism and specific molecular markers.
Main Methods:
- Adult wild-type and Akt2 knockout mice were administered propionate or vehicle orally for 7 days.
- Assessed cardiomyocyte contractile function, mitochondrial membrane potential, and performed oral glucose tolerance tests.
- Evaluated protein expression of key insulin-signaling molecules, short-chain fatty acid receptors (GPR41, GPR43), and protein phosphatases via Western blot.
Main Results:
- Akt2 knockout mice exhibited glucose intolerance, impaired cardiomyocyte contractility, and reduced mitochondrial membrane potential.
- Propionate treatment significantly improved cardiac function and mitochondrial potential in Akt2 knockout mice, except for glucose intolerance and GPR43 levels.
- Expression of GPR41 was decreased, while GPR43 was elevated in Akt2 knockout mice; propionate normalized GPR41 expression.
Conclusions:
- Akt2 deficiency leads to cardiomyocyte contractile and mitochondrial dysfunction.
- Dietary propionate demonstrates a beneficial effect against Akt2 deficiency-related cardiac anomalies.
- Short-chain fatty acids may represent a therapeutic strategy for Akt deficiency-induced cardiac issues.
