Nuclear factor-kappa B signaling in skeletal muscle atrophy

Abstract

Skeletal muscle atrophy/wasting is a serious complication of a wide range of diseases and conditions such as aging, disuse, AIDS, chronic obstructive pulmonary disease, space travel, muscular dystrophy, chronic heart failure, sepsis, and cancer. Emerging evidence suggests that nuclear factor-kappa B (NF-kappaB) is one of the most important signaling pathways linked to the loss of skeletal muscle mass in various physiological and pathophysiological conditions. Activation of NF-kappaB in skeletal muscle leads to degradation of specific muscle proteins, induces inflammation and fibrosis, and blocks the regeneration of myofibers after injury/atrophy. Recent studies employing genetic mouse models have provided strong evidence that NF-kappaB can serve as an important molecular target for the prevention of skeletal muscle loss. In this article, we have outlined the current understanding regarding the role of NF-kappaB in skeletal muscle with particular reference to different models of muscle wasting and the development of novel therapy.

Figure 1. Diagrammatic representation of NF-κB/IκB family proteins

The protein of NF-κB and IκB families along with their structural features are depicted here. The number of amino acids in each human protein is shown on right. TD, transactivation domain; N, nuclear localization sequence; LG, leucine zipper motif; and G, Glycine rich repeat.

Figure 2. Schematic representation of two NF-κB signaling pathways

Activation of NF-κB can occur by classical or alternative pathway. Classical pathway involves the activation of IKKβ leading to phosphorylation and degradation of IκBs. The alternative pathway involves IKKα and leads to the phosphorylation of processing of p100, generating p52:relB heterodimers. NIK, NF-κB-inducing kinase; Ub, ubiquitin; MEKK3, mitogen-activated protein kinase kinase kinase 3.

Figure 3. Putative mechanisms of action of NF-κB in skeletal muscle metabolism

Activation of NF-κB leads to muscle-wasting by multiple mechanisms. NF-κB can augment the expression of ubiquitin-proteasome system proteins (e.g. MURF1) and/or proinflammatory cytokines, chemokines, and tissue-degrading enzymes which leads to skeletal muscle-wasting. Activation of NF-κB can also induce muscle-wasting by blocking the process of myogenic differentiation possibly by modulating the levels of MyoD.

Figure 4. Role of NF-κB in different muscle-related disorders

Numerous studies have shown that the activation of NF-κB causes muscle-wasting in many disease states and conditions (shown in red). In LGMD2A, the NF-κB is essential for the survival of muscle fibers (shown in green). COPD, Chronic obstructive pulmonary disorder; DMD, Duchenne muscular dystrophy; LGMD2A, Limb-girdle muscular dystrophy type 2A.