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

Abstract

(150 -250 words) [165] 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 proliferatoractivated receptor  coactivators 1 (PGC-1) 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-B) 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.

Gene Expression Profiling in Slow-Type Calf Soleus Muscle of 30 Days Space-Flown Mice

“…Beyond the canonical role of PGC-1 in normal muscle plasticity and adaptation, it has been recently demonstrated that these coactivators are both able to reduce the pro-inflammatory cytokines production induced by TNFα or TLR agonists in normal skeletal muscle on the ground [38, 39]. We thus observed an increase in the expression of transcripts of several inflammatory chemokines in the soleus of the space-flown mice suggesting that components of the inflammatory response may play a role during extended microgravity-induced muscle atrophy.…”

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

“…Similarly, the massive muscle damage elicited by CTX injection leads to an elevation of immune cell activation as reported here. Thus, the interplay between muscle PGC-1α, inflammation, and immune cells is multi-faceted and highly context-dependent [33, 34]. …”

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

“…A tightly coordinated activation of tissue-resident and infiltrating immune cells is instrumental for proper muscle repair and regeneration after these recurring contraction-relaxation cycles. During this process, macrophages polarize into the M1-type inducing a pro-inflammatory cytokine profile to stimulate tissue clean-up1. This is followed by a second wave of M2 macrophage polarization that is linked to a predominantly anti-inflammatory milieu to boost tissue repair and regeneration1.…”

“…During this process, macrophages polarize into the M1-type inducing a pro-inflammatory cytokine profile to stimulate tissue clean-up1. This is followed by a second wave of M2 macrophage polarization that is linked to a predominantly anti-inflammatory milieu to boost tissue repair and regeneration1. In contrast to the transient inflammation after exercise, a persistent, low-grade elevation of pro-inflammatory factors, both locally in tissues as well as systemically, is closely associated with a number of chronic diseases, including the metabolic syndrome or cardiovascular pathologies1.…”