Tumor necrosis factor-α and muscle wasting: a cellular perspective

Abstract

commentary review reports research article COPD = chronic obstructive pulmonary disease; kDa = kiloDalton; MHCf = adult fast-type myosin heavy chain; NF-κB = nuclear factor-κB; NO = nitric oxide; ROS = reactive oxygen species; TNF-α = tumor necrosis factor-α; TNFR1 = type 1 TNF-α receptor; TNFR2 = type 2 TNF-α receptor.Available online http://respiratory-research.com/content/2/5/269 Introduction TNF-α is a polypeptide cytokine that promotes antitumor and immune responses [1]. TNF-α has long been associated with muscle pathology and was originally designated 'cachectin' in recognition of its catabolic action. Experimental animals lose muscle mass when treated with TNF-α [2,3] or exposed to interventions that elevate endogenous TNF-α (e.g. sepsis or tumor implantation). In humans, muscle catabolism has been attributed to TNF-α in inflammatory diseases that include cancer [4], congestive heart failure [5], AIDS [6], and chronic obstructive pulmonary disease (COPD) [7]. In the latter case, malnourished individuals with COPD have elevated serum levels of TNF-α [8] which may reflect exaggerated production by peripheral blood monocytes [9]. Loss of muscle mass contributes to weakness, fatigue, and loss of mobility for individuals with COPD and other inflammatory diseases. Despite its potential importance, the effects of TNF-α on skeletal muscle and the mechanisms of TNF-α action have remained largely undefined until recently. Cellular mechanism of TNF-α α action: a working modelThis commentary outlines the current perspective of the authors regarding TNF-α effects on differentiated muscle. Our concepts are summarized in an experimental model depicted in Figure 1.In brief, we propose that TNF-α can act directly on muscle cells to stimulate protein loss, an action mediated by nuclear factor-κB (NF-κB) which is a transcription factor. Intermediate steps in TNF-α/NF-κB signaling include stimulation of the type 1 TNF-α receptor (TNFR1) and an increase in reactive oxygen species (ROS) production via mitochondrial electron transport. NF-κB appears to increase activity of the ubiquitin/proteasome pathway, CommentaryTumor necrosis factor-α α and muscle wasting: a cellular perspective AbstractTumor necrosis factor-α (TNF-α) is a polypeptide cytokine that has been associated with muscle wasting and weakness in inflammatory disease. Despite its potential importance in muscle pathology, the direct effects of TNF-α on skeletal muscle have remained undefined until recently. Studies of cultured muscle cells indicate that TNF-α disrupts the differentiation process and can promote catabolism in mature cells. The latter response appears to be mediated by reactive oxygen species and nuclear factor-κB which upregulate ubiquitin/proteasome activity. This commentary outlines our current understanding of TNF-α effects on skeletal muscle and the mechanism of TNF-α action.

PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription

“…However, the mechanism for the surprising fall in PGC-1␣ in diverse catabolic states is unclear, and it represents an important question for study. The systemic muscle wasting in these conditions appears to be triggered by insulin resistance and͞or insulin deficiency (44), glucocorticoids (45), and͞or various monokines (46). The marked reduction in PGC-1␣ mRNA in atrophying muscles occurs where FoxO factors are activated (13) and expressed at high rates (7).…”

Myeloid cell‐derived tumor necrosis factor‐alpha promotes sarcopenia and regulates muscle cell fusion with aging muscle fibers

“…TNF‐α treatment of differentiated myotubes activates NFκB, which can lead to reductions in protein content (Li, Schwartz, Waddell, Holloway, & Reid, 1998). TNF‐α also induces the ubiquitin‐proteasome system in cachexia, which can be attenuated by blocking the activation of NFκB signaling (Reid & Li, 2001). TNF‐α can also decrease muscle protein content by inhibiting protein synthesis through the induction of IL‐6 or inhibition of insulin‐like growth factor‐I signaling (Alvarez et al, 2002; Frost, Lang, & Gelato, 1997).…”

Cytokine-induced Patterns of Gene Expression in Skeletal Muscle Tissue

“…Those same genes were transiently repressed in the animals pair-fed to leptin at days 3 and 5 with levels returning to base-line level at day 7. That cluster included three genes that play a role in protein catabolism, including a gene similar to the 20 S proteasome subunit RC6-I (a gene encoding a putative serine protease) and NFB (a known mediator of TNF-␣-induced muscle protein catabolism) (14,38). Those genes were also induced to a similar extent in the TNF-␣-treated animals (see the serine protease in Fig.…”

“…Most notably, TNF-␣ leads to the loss of muscle mass and cachexia, whereas chronic treatment with high doses of leptin spares lean body mass. TNF-␣ also reduces insulin sensitivity in skeletal muscle, whereas leptin enhances insulin action (3,4,8,11,13,14). Both leptin and TNF-␣ have been shown to act directly and indirectly on skeletal muscle to modulate muscle physiology (15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

“…Both leptin and TNF-␣ have been shown to act directly and indirectly on skeletal muscle to modulate muscle physiology (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). TNF-␣ stimulates muscle catabolism leading to the loss of muscle function in human diseases that range from cancer to heart failure, from arthritis to AIDS (13,14,(25)(26)(27). Leptin acts directly on skeletal muscle to increase fatty-acid oxidation via an 5Ј-AMP-activated protein kinase-dependent inhibition of acetyl coenzyme A carboxylase (28).…”