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

https://doi.org/10.1016/j.bbrc.2015.06.166Get rights and content

Highlights

  • Muscle PGC-1s are insufficient to prevent acute systemic inflammation.

  • The muscle PGC-1s however promote a local anti-inflammatory environment.

  • This anti-inflammatory environment could contribute to the therapeutic effect of the PGC-1s.

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.

Introduction

Metabolic and immune pathways intersect at multiple levels in the human body, both in the healthy but maybe even more importantly in the diseased state often with detrimental consequences. For example, a metabolic imbalance in obesity not only leads to metabolic dysregulation, but also a chronic systemic inflammation [1], [2], [3]. The latter event often originates from fat tissue with pronounced accumulation of pro-inflammatory macrophages (also referred to as classically activated or M1 macrophages) [4]. These macrophages release large quantities of pro-inflammatory cytokines, e.g. tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and monocyte chemotactic protein 1 (MCP-1), that further foster inflammation [5], [6]. In contrast, adipose tissue of lean animals and humans harbors mainly alternatively activated (or M2) macrophages that express a distinct set of anti-inflammatory cytokines, e.g. C–C motif chemokine 1 (CCL1), CCL22, IL-1 receptor antagonist (IL-1Ra), transforming growth factor β (TGFβ), and IL-10 [5]. While M1 macrophages drive inflammation and are thus physiologically important during the innate immune response against pathogens, M2 macrophages constrain and modulate inflammatory reactions in the resolution of inflammation, tissue remodeling and repair.

The aberrant activation of M1 macrophages in obesity is not only seen in adipose tissue but also – in other peripheral organs such as liver or skeletal muscle. Obesity promotes the build-up of intramuscular adipose depots and, analogous to fat tissue, M1-type macrophage accumulation [4]. This chronic low grade inflammation contributes to the development of insulin resistance, a hallmark of diabetes. . Similar to diet-induced weight loss, regular exercise also counteracts type 2 diabetes and limits systemic inflammation [7], [8]. An important factor mediating many of the beneficial effects of exercise is the PPARγ coactivator 1α (PGC-1α) [9], [10]. PGC-1α and the related PGC-1β coactivate an array of nuclear receptors and transcription factors in skeletal muscle to induce the transcription of genes involved in mitochondrial biogenesis and oxidative phosphorylation and thereby enable a higher endurance capacity [11], [12]. Mice with skeletal muscle-specific overexpression of PGC-1α (MCKα mice) consequently score better in running tests and have a larger proportion of slow-twitch type I and IIa fibers than wild-type (WT) littermates [13], [14]. Mice with transgenic overexpression of PGC-1β (MCKβ mice) also exhibit lower fatigability but unlike the MCKα mice, a switch towards IIx fibers [15]. Inversely, skeletal muscle-specific deletion of PGC-1α [16] or of PGC-1β [17] results in poorer running performance.

In contrast to the elevated levels of PGC-1α in endurance athletes, the expression of PGC-1α and PGC-1β is reduced in skeletal muscle of human diabetic patients with a coordinate depression of mitochondrial oxidative phosphorylation, at least in certain populations [18], [19]. Importantly, in these patients, PGC-1α levels inversely correlate with the pro-inflammatory cytokines IL-6 and TNFα independent of body mass index (BMI) [20]. This suggests a mutual negative relationship between PGC-1 coactivators and inflammation in skeletal muscle.

Further experimental evidence for such a link derives from mice with skeletal muscle-specific PGC-1α deletion that exhibit elevated levels of muscle and systemic inflammation [20]. Accordingly, PGC-1α and PGC-1β overexpression constrains pro-inflammatory cytokine expression upon TNFα exposure by inhibiting the transcriptional activity of nuclear factor κB (NF-κB) in muscle cells in vitro [21]. Inversely, classical NF-κB activation in muscle cells dampens the expression of proteins involved in oxidative phosphorylation, including PGC-1α and PGC-1β [22]. Thus, an inverse regulation between the PGC-1 coactivators and pro-inflammatory gene expression exists in muscle cells. In the present study, we expanded the in vitro findings and now explored this mutual negative relationship in vivo. Specifically, we defined the role of PGC-1α and PGC-1β overexpression in skeletal muscle on local and systemic inflammatory events triggered by injection of the inflammatory agents lipopolysaccharide (LPS) and TNFα. Thereby, the previously reported muscle cell autonomous effects of the PGC-1 coactivators in cell culture models can be separated from the consequences of muscle fiber-specific elevation of PGC-1α and PGC-1β on different cell types, including immune cells in muscle tissue in vivo. Intriguingly, we observed that elevation of the PGC-1 coactivators promotes an anti-inflammatory environment in muscle.

Section snippets

Mice and treatments

C57BL/6 mice expressing PGC-1α (MCKα) [14] and FVB/N mice expressing PGC-1β (MCKβ) [15] under the control of the muscle creatine kinase (MCK) promoter were bred with respective WT mice to obtain WT and transgenic littermates. Male mice were maintained on a standard rodent chow with 12 h light/dark cycle and subjected to experiments at 8–12 weeks of age. Injections were performed under sevoflurane anesthesia. Mice were randomly assigned to one experimental group and subsequently injected

Muscle PGC-1α and PGC-1β do not suppress systemic pro-inflammatory factors after LPS/TNFα injection in vivo

To delineate the role of skeletal muscle PGC-1 in an acute inflammatory insult in vivo, we injected bacterial LPS, TNFα or PBS as vehicle control i.m. into the tibialis anterior (TA) muscle of wildtype (WT) control, PGC-1α (MCKα) and PGC-1β (MCKβ) muscle-specific transgenic animals. Importantly, separate WT control cohorts were used to reflect the difference in the mouse strain background (C57BL/6 for MCKα, FVB/N for MCKβ). After 4 h, the animals were sacrificed, blood collected and the TA

Discussion

Metabolism and inflammation are two biological processes that are tightly linked. We now report that PGC-1α and PGC-1β constitute a molecular link between metabolism and inflammation in skeletal muscle. Strikingly, these two PGC-1 coactivators alter the inflammatory environment with a corresponding muscle cytokine expression profile. In particular, anti-inflammatory factors such as CCL1, CCL22, IL-1Ra, TGFβ or IL-10 were elevated in one or both muscle-specific overexpression models depending on

Author contributions

P.S.E. designed and performed experiments, analyzed data and wrote the paper; R.F. wrote the paper; M.B. performed experiments; and C.H. supervised the study and wrote the paper.

Conflict of interests

The authors declare that they have no conflict of interests.

Acknowledgments

We thank Prof. Christoph Hess for critical reading of the manuscript. This project was funded by the Swiss National Science Foundation grant 310030_156654, the Swiss Society for Research on Muscle Diseases (SSEM), the ERC Consolidator grant 616830-MUSCLE_NET, Systems X.ch and the University of Basel.

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    Present address: Labor Team W, Goldach, Switzerland.

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