The PGC-1 coactivators promote an anti-inflammatory environment in skeletal muscle in vivo

Abstract

The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is abundantly expressed in trained muscles and regulates muscle adaptation to endurance exercise. Inversely, mice lacking a functional PGC-1α allele in muscle exhibit reduced muscle functionality and increased inflammation. In isolated muscle cells, PGC-1α and the related PGC-1β counteract the induction of inflammation by reducing the activity of the nuclear factor κB (NFκB). We now tested the effects of these metabolic regulators on inflammatory reactions in muscle tissue of control and muscle-specific PGC-1α/-1β transgenic mice in vivo in the basal state as well as after an acute inflammatory insult. Surprisingly, we observed a PGC-1-dependent alteration of the cytokine profile characterized by an increase in anti-inflammatory factors and a strong suppression of the pro-inflammatory interleukin 12 (IL-12).In conclusion, the anti-inflammatory environment in muscle that is promoted by the PGC-1s might contribute to the beneficial effects of these coactivators on muscle function and provides a molecular link underlying the tight mutual regulation of metabolism and inflammation.

Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

“…1C). As reported previously11, IL-12 levels were strongly suppressed by PGC-1α overexpression. In contrast to the mixed M1 cytokine expression pattern, all of the tested M2 cytokines were significantly augmented by PGC-1α overexpression (Fig.…”

“…In cultured muscle cells, overexpression of PGC-1α exerts a dampening of nuclear factor κB activity and consequently a suppression of pro-inflammatory gene expression upon treatment with tumor necrosis factor α (TNFα), saturated fatty acids or specific activators of the toll-like receptors 1/2, 4 and 6/210. In contrast, specific PGC-1α overexpression in muscle fibers in vivo was not able to reduce the strong, acute inflammation induced by TNFα or bacterial lipopolysaccharide (LPS), indicating a cross-talk of different cell types to overcome the cell autonomous anti-inflammatory effect of PGC-1α in muscle tissue11. These findings imply a multifaceted role for muscle PGC-1α to modulate local inflammation that extends beyond cell autonomous effects with important implications for our understanding of muscle cell plasticity in exercise and disease.…”

PGC-1α modulates necrosis, inflammatory response, and fibrotic tissue formation in injured skeletal muscle

“…Importantly however, in other contexts, the intrinsic effects of PGC-1α on muscle inflammation is most likely masked by the much higher levels of these genes in resident and infiltrating immune cells. For example, in mice exposed to strong pro-inflammatory stimuli, PGC-1α modulation in skeletal muscle affects the expression of pro- and anti-inflammatory genes [31, 32]. Similarly, the massive muscle damage elicited by CTX injection leads to an elevation of immune cell activation as reported here.…”

PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments

“…Over-expression in muscle protects mice from disease, exercise, and age-related inflammatory damage [15][16][17][18] and preservation of PGC-1α activity blunts lipopolysaccharide (LPS)-induced inflammatory damage to heart and kidney 19,20 . On the other hand, reduced PGC-1α increases pro-inflammatory cytokine expression and increases inflammation damage to muscle and liver tissue in response to stresses 17,21,22 . Over-expression of PGC-1α decreases expression of pro-inflammatory cytokines, while simultaneously inducing expression of secreted anti-inflammatory factors 17,23 .…”

“…On the other hand, reduced PGC-1α increases pro-inflammatory cytokine expression and increases inflammation damage to muscle and liver tissue in response to stresses 17,21,22 . Over-expression of PGC-1α decreases expression of pro-inflammatory cytokines, while simultaneously inducing expression of secreted anti-inflammatory factors 17,23 . How PGC-1α regulates inflammatory responses and effects of this within cells is not yet understood.…”