IL-6 and IGF-1 Signaling Within and Between Muscle and Bone: How Important is the mTOR Pathway for Bone Metabolism?

Abstract

Insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6) play an important role in the adaptation of both muscle and bone to mechanical stimuli. Here, we provide an overview of the functions of IL-6 and IGF-1 in bone and muscle metabolism, and the intracellular signaling pathways that are well known to mediate these functions. In particular, we discuss the Akt/mammalian target of rapamycin (mTOR) pathway which in skeletal muscle is known for its key role in regulating the rate of mRNA translation (protein synthesis). Since the role of the mTOR pathway in bone is explored to a much lesser extent, we discuss what is known about this pathway in bone and the potential role of this pathway in bone remodeling. We will also discuss the possible ways of influencing IGF-1 or IL-6 signaling by osteocytes and the clinical implications of pharmacological or nutritional modulation of the Akt/mTOR pathway.

Fig. 1

Insulin-like 1 (IGF-1) and interleukin-6 (IL-6) signaling in the regulation of skeletal muscle adaptation and bone metabolism. a In skeletal muscle, the machinery for protein synthesis and degradation resides within the muscle fibers, which are multinucleated cells. The muscle satellite cells (MuSCs) reside between the sarcolemma (i.e., plasma membrane) and the basal lamina. b In bone, osteoid is synthesized by osteoblasts (OB) which are derived from osteogenic progenitor cells and differentiate into osteocytes (OC) when buried in their own matrix. Osteocytes have long extensions embedded within the canaliculi and are highly sensitive to mechanical loading. In response to mechanical stimuli, myofibers (MF) produce paracrine/endocrine factors such as IL-6, and both splice variants of IGF-1, i.e., mechano growth factor (MGF) and IGF-1Ea. These factors are able to affect myofibers, MuSCs, and cells in other organs such as the liver and potentially bone. IL-6 slows down the rate of translation in myofibers while enhancing the rate of protein breakdown via 5′ adenosine monophosphate-activated protein kinase (AMPK), resulting in a net catabolic effect. On the other hand, IL-6 stimulates the proliferation and differentiation of satellite cells via the Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, which would be an anabolic response. IGF-1 stimulates the rate of protein translation in myofibers via the phosphatidylinositol 3 kinase (PI3-K)/Akt/mammalian target of rapamycin (mTOR) pathway while inhibiting the expression of catabolic ubiquitin E3 ligases resulting in an increase in muscle mass. MGF stimulates satellite cell proliferation and differentiation, but it is so far unclear via which pathway this occurs. Mechanically-loaded osteocytes and osteoblasts produce IGF-1 (likely both splice variants), and IGF-1 is released from the matrix during osteoclastic (OCL) bone resorption. Mechanically-loaded osteocytes and osteoblasts also produce IL-6, as do apoptotic osteocytes. IGF-1 enhances differentiation of osteoblast precursors cells (OBPC) via the PI3-K/AktT/mTOR pathway (not shown) and activity and formation of osteoclasts via stimulation of RANKL expression in osteoblasts and osteocytes. IL-6 also stimulates osteoblast precursor differentiation and osteoclast formation, via an increase in RANKL expression by osteoblasts. Whether IL-6 and IGF-1 affect the rate of protein translation in osteoblasts or osteoclasts is currently unknown. IRS-1 insulin receptor substrate-1; eIF4E eukaryotic initiation factor 4E; 4E-BP eIF4E-binding protein; p70S6K p70S6 kinase; eIF2B eukaryotic initiation factor 2B. GSK3β glycogen synthase kinase 3β