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

Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) also has a profound effect on cytokine expression in muscle tissue. Muscle PGC-1α expression results in activation of tissue-resident macrophages, at least in part mediated by PGC-1α-dependent B-type natriuretic peptide (BNP) production and secretion. Positive effects of exercise in metabolic diseases and other pathologies associated with chronic inflammation could accordingly involve the PGC-1α-BNP axis and thereby provide novel targets for therapeutic approaches.

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology.

Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferator-activated receptor γ coactivators 1 (PGC-1s) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that, in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-κB) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications.

The peroxisome proliferator-activated receptor γ coactivator 1α/ß (PGC-1) coactivators repress the transcriptional activity of NF-κB in skeletal muscle cells.

A persistent, low-grade inflammation accompanies many chronic diseases that are promoted by physical inactivity and improved by exercise. The beneficial effects of exercise are mediated in large part by peroxisome proliferator-activated receptor γ coactivator (PGC) 1α, whereas its loss correlates with propagation of local and systemic inflammatory markers. We examined the influence of PGC-1α and the related PGC-1ß on inflammatory cytokines upon stimulation of muscle cells with TNFα, Toll-like receptor agonists, and free fatty acids. PGC-1s differentially repressed expression of proinflammatory cytokines by targeting NF-κB signaling. Interestingly, PGC-1α and PGC-1ß both reduced phoshorylation of the NF-κB family member p65 and thereby its transcriptional activation potential. Taken together, the data presented here show that the PGC-1 coactivators are able to constrain inflammatory events in muscle cells and provide a molecular link between metabolic and immune pathways. The PGC-1s therefore represent attractive targets to not only improve metabolic health in diseases like type 2 diabetes but also to limit the detrimental, low-grade inflammation in these patients.

Distinct motifs in the chemokine receptor CCR7 regulate signal transduction, receptor trafficking and chemotaxis.

The chemokine receptor CCR7, together with its ligands CCL19 and CCL21, is responsible for the correct homing and trafficking of dendritic cells and lymphocytes to secondary lymphoid tissues. Moreover, cancer cells can utilize CCR7 to metastasize to draining lymph nodes. However, information on CCR7 signaling leading to cell migration or receptor trafficking is sparse. Using novel CCR7 deletion mutants with successive truncations of the intracellular C-terminus and a mutant with impaired G-protein coupling, we identified distinct motifs responsible for various aspects of CCR7 signal transduction. Deleting a Ser/Thr motif at the tip of the intracellular tail of CCR7 resulted in an impaired chemokine-mediated activation of Erk1/2 kinases. Interestingly, deleting an additional adjacent motif restored the ability of CCL19-mediated Erk1/2 phosphorylation, suggesting the presence of a regulatory motif. Both the Ser/Thr and the regulatory motif are dispensable for signaling events leading to cell migration and receptor trafficking. A CCR7 mutant lacking virtually the complete C-terminus readily bound CCL19 and was internalized, but was unable to activate the G protein and to transmit signals required for cell migration, mobilization of [Ca2+](i) and Erk1/2 activation. Finally, G-protein coupling was critical for [Ca2+](i) mobilization, Erk1/2 phosphorylation and chemotaxis, but not for CCR7 trafficking.