Regulator of Inflammation TGF-β1 Contributes to Muscle Atrophy in Aging
Inflammatory signaling disrupts all sorts of normal tissue functions. In the short term this is usually beneficial; inflammation is a necessary part of wound healing, defense against pathogens, and even destruction of errant cells. It is required to mobilize the immune system and coordinate the activities of various classes of immune cell with those of other cell populations. Unfortunately inflammation becomes chronic in later life, and the constant inflammatory signaling - and cellular reactions to that signaling - degrades normal function and produces lasting damage as a result. This particularly noteworthy when it comes to loss of regenerative capacity and generation of harmful fibrosis.
Chronic inflammation in aging and disease has long been a topic of interest for the research community, and a great deal of effort has been put into trying to understand the fine details of inflammation and means to control it. The newfound acceptance of the past few years that accumulation of senescent cells and growth in their potent inflammatory signaling is a significant cause of degenerative aging has only reinforced this part of the field.
"Inflammatory signaling" is, however, a very broad category. The processes of inflammation are very complicated, as is true of any situation in which multiple types of cell are interacting with one another. It is rarely the case that researchers can point to any one protein and say that more of it is always a bad thing. Context and timing and location all matter. Further, many inflammatory signal proteins have roles other than that related directly to the immune system - evolution is very much in favor of promiscuous reuse of component parts that happen to be lying around. TGF-β1 is a good example. It can increase or decrease inflammatory activity in specific contexts, and while it is definitely a prominent part of the problem of chronic inflammation in later life, it cannot simply be suppressed without unwelcome side-effects, the loss of activities that are still beneficial even in the context of a damaged immune system.
It is challenging (meaning expensive and slow) to unravel the complexity of metabolism, even in the context of a well researched single protein, in order to arrive at therapies that override dysfunction in some way. This is precisely why we should avoid messing with metabolism, investing in this process of trying to find overrides in a poorly understood, complex system. Instead, the focus should be on examining the root causes of this dysfunction. Find ways to repair or remove the cell and tissue damage that leads to chronic inflammation and the pathological state of the aged immune system. When damage is meaningfully repaired, then a complex system will revert on its own to a more functional, youthful state.
Transforming growth factor type beta 1 (TGF-β1) is a growth factor and cytokine belonging to a superfamily of ligands, including bone morphogenetic proteins (BMPs), growth and differentiation factors, activins and myostatin, which are pleiotropic factors with important roles in inflammation, cell growth, and tissue repair. TGF-β1 mediates many of its intracellular actions by changes in the gene expression to regulate the synthesis of extracellular matrix (ECM) proteins, cell motility and several cellular processes, including differentiation, renewal, and quiescence. In skeletal muscle, TGF-β1 can be activated and/or up-regulated by different stimuli, such as acute skeletal muscle injury, or in other cases by chronic stimulus generated in different types of skeletal muscle diseases in which fibrosis and/or atrophy is produced.
Skeletal muscle is a tissue that has the capacity to regenerate after damage, with the replacement of injured tissue by healthy and functional tissue. The regenerative capacity of adult skeletal muscle is attributed to a population of resident stem cells called satellite cells (SC). In normal conditions, SCs are in a quiescent status. However, after damage or in response to degenerative stimuli, the activation of SCs is induced. The formation of mature myofibers and the regeneration process can be impaired or arrested by several mechanisms, such as the inhibition of cell cycle entry, increment of cell death and/or premature terminal commitment. TGF-β1 is a typical inhibitor of the myogenic differentiation process because it can cause SC apoptosis and potently inhibit its proliferation and fusion, negatively affecting muscle regeneration. In this context, in aged regenerating skeletal muscle, TGF-β1 signalling is abnormally elevated and considered to inhibit SC activation and terminal myogenic differentiation.
Fibrosis is formed by the accumulation of ECM proteins, such as fibronectin, collagen, elastin, and laminin, among others, which are produced within the tissue via activation of different fibrogenic factors or cytokines, such as TGF-β1. In several muscular dystrophies, the synthesis and accumulation of ECM components produce the progressive replacement of functional muscle tissue by connective tissue, with the consequent loss of muscle function. Several reports have shown that TGF-β1 has a key role in the inflammatory process in skeletal muscle and induces muscle fibrosis by increasing collagen, fibronectin and other profibrotic factors, such as connective tissue growth factor (CTGF).
The increased knowledge about the participation of TGF-β1 in several muscular pathologies has attracted great interest in the evaluation of therapeutic alternatives to neutralise or diminish the deleterious effects of TGF-β1. Among the possible strategies to inhibit TGF-β signalling are blocking antibodies for TGF-β1, and the different components of RAS and several inhibitors of the TGF-β1 receptors or signalling pathway have been proposed. The main problem with the use of therapies aiming at inhibiting TGF-β1 signalling is the lack of specificity of the compounds and therefore the development of side effects. The challenge is to develop therapy that can specifically promote muscle regeneration while decreasing fibrosis and atrophy without altering the normal function of TGF-β in other tissues, such as regulation of proliferation, haematopoiesis, migration, or inflammation.