Leptin Administration Favors Muscle Mass Accretion by Decreasing FoxO3a and Increasing PGC-1α in ob/ob Mice

Neira Sáinz,Gema Frühbeck,Amaia Rodríguez,Sara Becerril,Victoria Catalán,Javier Gómez-Ambrosi,Beatriz Ramírez,Jose A L Calbet

doi:10.1371/journal.pone.0006808

Abstract

Absence of leptin has been associated with reduced skeletal muscle mass in leptin-deficient ob/ob mice. The aim of our study was to examine the effect of leptin on the catabolic and anabolic pathways regulating muscle mass. Gastrocnemius, extensor digitorum longus and soleus muscle mass as well as fiber size were significantly lower in ob/ob mice compared to wild type littermates, being significantly increased by leptin administration (P<0.001). This effect was associated with an inactivation of the muscle atrophy-related transcription factor forkhead box class O3 (FoxO3a) (P<0.05), and with a decrease in the protein expression levels of the E3 ubiquitin-ligases muscle atrophy F-box (MAFbx) (P<0.05) and muscle RING finger 1 (MuRF1) (P<0.05). Moreover, leptin increased (P<0.01) protein expression levels of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a regulator of muscle fiber type, and decreased (P<0.05) myostatin protein, a negative regulator of muscle growth. Leptin administration also activated (P<0.01) the regulators of cell cycle progression proliferating cell nuclear antigen (PCNA) and cyclin D1, and increased (P<0.01) myofibrillar protein troponin T. The present study provides evidence that leptin treatment may increase muscle mass of ob/ob mice by inhibiting myofibrillar protein degradation as well as enhancing muscle cell proliferation.

Highlights

Leptin, the product of the ob gene, is a hormone that acts as an afferent signal in a negative-feedback loop regulating the size of adipose tissue mass [1]
ubiquitin-proteasome system (UPS) induces the expression of the ubiquitin ligases E3 muscle atrophy F-box (MAFbx, known as atrogin-1) and muscle RING finger-1 (MuRF1)
Our study shows an up-regulation of positive regulators of muscle growth and cell cycle progression in GAS muscle of leptin-treated ob/ob mice (Igf1, Igfbp5, Notch3, Ccnd1, Clk4, Cited4, Cdc14a), and myoblast differentiation (Eya1, Mkl1, Srf), whereas negative regulators of cell cycle progression, such as Cdkn1a/p21, Cdkn1b/ p27Kip1 or Rbl2, were down-regulated by leptin administration in ob/ob mice

Summary

Introduction

The product of the ob gene, is a hormone that acts as an afferent signal in a negative-feedback loop regulating the size of adipose tissue mass [1]. UPS induces the expression of the ubiquitin ligases E3 muscle atrophy F-box (MAFbx, known as atrogin-1) and muscle RING finger-1 (MuRF1) These ubiquitin ligases target proteins with a ubiquitin chain to be subsequently degraded within the proteasome complex to peptides [7]. Another key mediator in protein breakdown during atrophy is the forkhead box class O (FoxO) family of transcription factors [10] In this sense, FoxO1 and FoxO3a, which are highly expressed in skeletal muscle, induce muscle mass loss by increasing the expression of MAFbx and MuRF1 [11,12,13], by inhibiting muscle growth and differentiation [14] and by impairing the progression of the cell cycle [15]. It has been reported that peroxisome proliferator-activated receptor coactivator 1a (PGC-1a) constitutes an important mediator of muscle mass down-regulating the expression levels and activity of FoxO3a and, inhibiting muscle atrophy [19]

Objectives

Methods

Results

Conclusion