Abstract
Androgens are primarily involved in muscle growth, whilst disease-driven muscle wasting is frequently associated with hypogonadism. The Leydig cells of the testes also produce the peptide-hormone Insulin-like peptide 3 (INSL3). INSL3 displays anabolic activity on bone, a target tissue of androgens, and its plasma concentrations are diminished in male hypogonadism. Here we tested the role of INSL3 on muscle mass regulation, in physiological and pathological conditions. Studies on C2C12 cell line showed that INSL3, acting on his specific receptor RXFP2, promotes skeletal muscle protein synthesis through the Akt/mTOR/S6 pathway. Next, studies on Rxfp2−/− mice showed that INSL3 is required to prevent excessive muscle loss after denervation. Mechanistically, denervated Rxfp2−/− mice lacked the compensatory activation of the Akt/mTOR/S6 pathway and showed an abnormal ubiquitin-proteasome system activation. Lack of INSL3 activity resulted also in reduced contractile force. These findings underlie a role of INSL3/RXFP2 in protein turnover, contributing to muscle wasting in male hypogonadism.
Highlights
The skeletal muscle mass is regulated by the coordinated balance between rates of protein synthesis and protein breakdown
In order to study the possible role of Insulin-like peptide 3 (INSL3)/RXFP2 signaling pathway in skeletal muscle, we firstly evaluated the RXFP2 expression and function in the C2C12 muscle cell line (Figure 1)
RXFP2 was much less expressed in myoblasts and, in vitro stimulation of C2C12 myoblasts with INSL3 up to 72h, at concentrations ranging from 0 to 100 nM, had negligible effect on cell proliferation assessed by MTT test (Supplemental Figure 1A)
Summary
The skeletal muscle mass is regulated by the coordinated balance between rates of protein synthesis and protein breakdown. The decrease in muscle mass and fiber size is associated with a number of clinical conditions, from aging and starvation to disuse, cancer and altered hormonal pattern [1, 2]. Androgens represent the class of sex steroids with a major involvement in muscle mass growth [3, 4]. From a clinical point of view, reduced muscle mass and strength represent major manifestations that raise suspicion of T deficiency [6]. T loss in male mice decreases muscle Igf mRNA, Akt phosphorylation and the rate of myofibrillar protein synthesis and these changes are all reversed by androgen treatment [3]
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