Metformin Increases Protein Phosphatase 2A Activity in Primary Human Skeletal Muscle Cells Derived from Lean Healthy Participants.

Aktham Mestareehi,Abdullah Mallisho,Zhengping Yi,Zaher Msallaty,Xiangmin Zhang,Berhane Seyoum,Anjaneyulu Kowluru,Kyle Jon Burghardt,Maria Mirabelli

doi:10.1155/2021/9979234

Abstract

Objective To investigate if PP2A plays a role in metformin-induced insulin sensitivity improvement in human skeletal muscle cells. Participants. Eight lean insulin-sensitive nondiabetic participants (4 females and 4 males; age: 21.0 ± 1.0 years; BMI: 22.0 ± 0.7 kg/m2; 2-hour OGTT: 97.0 ± 6.0 mg/dl; HbA1c: 5.3 ± 0.1%; fasting plasma glucose: 87.0 ± 2.0 mg/dl; M value; 11.0 ± 1.0 mg/kgBW/min). Design A hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity in human subjects, and skeletal muscle biopsy samples were obtained. Primary human skeletal muscle cells (shown to retain metabolic characteristics of donors) were cultured from these muscle biopsies that included 8 lean insulin-sensitive participants. Cultured cells were expanded, differentiated into myotubes, and treated with 50 μM metformin for 24 hours before harvesting. PP2Ac activity was measured by a phosphatase activity assay kit (Millipore) according to the manufacturer's protocol. Results The results indicated that metformin significantly increased the activity of PP2A in the myotubes for all 8 lean insulin-sensitive nondiabetic participants, and the average fold increase is 1.54 ± 0.11 (P < 0.001). Conclusions These results provided the first evidence that metformin can activate PP2A in human skeletal muscle cells derived from lean healthy insulin-sensitive participants and may help to understand metformin's action in skeletal muscle in humans.

Highlights

In the US, ∼30 million individuals have type 2 diabetes (T2D), which is associated with long-term damage of various organs
phosphatase 2A (PP2A) activity measurement indicated that metformin increased the activity of PP2A in the myotubes derived from all eight lean nondiabetic participants as presented in Figures 1(b) and 1(c)
These results provided the first evidence that metformin promotes activation of PP2A in human skeletal muscle cells derived from lean, insulin-sensitive, nondiabetic participants

Summary

Introduction

In the US, ∼30 million individuals have type 2 diabetes (T2D), which is associated with long-term damage of various organs (e.g., eyes, kidneys, nerves, heart, and brain). Insulin resistance in skeletal muscle is one of the main causes for T2D [1]. Links between insulin resistance, diabetes, and brain disorders have been reported [4, 5], and metformin has been shown to have antiseizure effects in epilepsy animal models and is proposed as a potential candidate for drug repurposing for epilepsy patients [5,6,7]. Metformin may activate PP2A [9, 10], while others have shown that metformin has no effect on PP2A [11]. Whether metformin affects PP2A activity in primary human skeletal muscle cells remains to be elucidated. The overall objective of this study was to determine whether metformin activates PP2A in primary human skeletal muscle cells

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Results

Discussion

Conclusion