My laboratory has a long-standing interest in the characterization of a family of mammalian genes that we identified more than a decade ago. This gene family encodes proteins called the inhibitors of apoptosis (IAPs), which suppress the programmed cell death (apoptosis) of cells under both normal and disease conditions.
A major mechanism by which IAPs inhibit apoptosis is through the repression of the function of a family of proteases, known as caspases, that are activated under stress to dismantle cells and induce their death in an orderly fashion. Recently, it has been found been found that IAPs can also block apoptosis through other non-caspase-dependent means. Specifically, IAPs can also function as key regulatory signaling molecules in survival and cell death pathways.
Over the years, we have studied the fundamental aspects of the regulation of apoptosis by IAPs in normal physiological processes and in the development of various diseases, including cancer, neurodegeneration, autoimmune disease, and neuromuscular disorders. We have become increasingly interested in determining the basic roles of IAPs in skeletal muscle and in disease states such as muscular dystrophy and skeletal muscle atrophy. Three of the mammalian IAPs—cellular IAP1 and -2 (cIAP1, cIAP2) and X-linked IAP (XIAP)—are expressed in muscle, but little is known about their specific functions. cIAP1 and cIAP2 are members of tumor necrosis factor receptor (TNFR)–associated signaling complexes, which have both pro- and anti-apoptotic activities. This is of particular interest in skeletal muscle, where TNF-alpha plays a fundamental role in inflammation and regeneration upon injury or adaptation. The anti-apoptotic arm of the TNF-alpha signaling pathways depends on activation of the transcription factor, NF-kB. cIAP1 and cIAP2 are believed to participate in NF-kB activation, but the exact mechanisms remain unknown. Furthermore, the importance of these pathways in muscle and the role of IAPs have not been investigated; hence, this aspect has become a major focus of our current research efforts.
Recently, intriguing studies have shown that NF-kB is chronically activated in atrophic and dystrophic muscle and is a major contributor to pathology, identifying it as a therapeutic target of high priority. However, there is, as yet, no reconciliation between the pro-survival role of NF-kB in normal cells and its degenerative effects in disease muscle. Thus, the long-term consequences of blocking its activity are unknown. Our recent data conclusively demonstrate that cIAP1 regulates NF-kB in myoblasts and promotes survival upon TNF-alpha stimulation. Furthermore, cIAP1 is required for myoblast differentiation. Previously, we found that cIAP2 promotes a sustained inflammatory response by enhancing the survival of macrophages in the face of high levels of TNF-alpha. cIAP2 transcription is induced by NF-kB and thus it may also be chronically induced in atrophic and dystrophic muscle. Together, our studies demonstrate that IAPs have an essential role in myoblasts and strongly implicate them in the control of cell survival and differentiation during muscle regeneration. We want to better understand the mechanisms that control skeletal muscle regeneration in acute and chronic inflammatory settings. In addition to providing insights into muscle homeostasis, these studies will allow a more informed approach toward the targeting of specific molecules, such as NF-kB, involved in the chronic cycles of degeneration and regeneration that occur in muscle disease.
Last updated October 2008