Exercise and PGC-1α in Inflammation and Chronic Disease
Körperliche Aktivität und PGC-1alpha bei Entzündung und chronischen Krankheiten
A sedentary lifestyle is a strong and independent risk factor for many chronic diseases. In most cases, inadequate levels of physical activity are linked to a persistent, sterile inflammation, both locally in various organs as well as systemically. Inversely, exercise is an efficient intervention for the prevention and treatment of various pathologies.
Despite this obvious importance, the molecular mechanismsthat underlie exercise-induced health benefits remain largely unclear.
In recent years, the peroxisome proliferator-activated receptor γcoactivator 1α(PGC-1α) has emerged as a regulatory nexus of muscle adaptation to endurance exercise. Muscle PGC-1αnot only promotes an oxidative, slow-twitch muscle fiber type, but also modulates the phenotype of non-muscle cells. For example, activation of epithelial cells contributes to PGC-1α-controlled muscle vascularization. Similarly, muscle PGC-1α-dependent signaling results in remodeling of the active zone of motor neurons at the neuromuscular junction. Intriguingly, PGC-1αalso reduces pro-inflammatory gene expression in muscle and most likely other cell types. Thus, a bidirectional negative regulation of PGC-1αand the nuclear factor κB (NF-κB) might provide the molecular basis for the mutual antagonism between oxidative metabolism and inflammation in muscle.
In this review, we summarize the regulation and function of these transcriptional regulators with a particular focus on exercise and inflammation in skeletal muscle.
KEY WORDS: Skeletal Muscle, Exercise, Metabolism, Inflammation, PGC-1α
Ein inaktiver Lebensstilist ein starker und unabhängiger Risikofaktor für die Entstehung einer Reihe von chronischen Krankheiten. In vielen Fällen ist ungenügende Bewegung mit erhöhten Entzündungsmarkern verbunden, sowohl in einzelnen Organen wie auch systemisch im ganzen Körper. Umgekehrt entfaltet körperliche Aktivität und Training in der Prävention und Behandlung von verschiedenen Krankheiten eine große Wirkung.
Trotz dieser klinisch relevanten Beobachtungsind die molekularen Vorgänge, die den therapeutischen Effekt von Training auslösen und kontrollieren, noch weitgehend unbekannt.
In den letzten Jahrenhat sich das Koaktivatorprotein PGC-1α(peroxisome proliferator-activated receptor γcoactivator 1α) als ein zentraler Regulator in der Anpassung des Skelettmuskels an Ausdauertraining herausgestellt. Neben der Förderung von oxidativen, langsam kontrahierenden Muskelfasern löst PGC-1αauch Änderungen in anderen Zelltypen aus. So wird zum Beispiel durch eine Aktivierung von Epithelzellen die Bildung von Blutgefäßen im Muskel durch PGC-1αinduziert. Weiter hat PGC-1αim Muskel einen Einfluss auf Motorneuronen, wenigstens lokal im Bereich der neuromuskulären Synapse. Interessanterweise kontrolliert PGC-1αim Muskel und wahrscheinlich auch in anderen Zelltypen anti-entzündliche Reaktionen. Eine gegenseitige funktionelle Unterdrückung der Aktivitäten von PGC-1αund NF-κB (nuclear factor κB)könnte so die molekulare Schnittstelle darstellen, die die reziproke Regulation von Metabolismus und Entzündung im Muskel bestimmt.
In diesem Übersichtsartikelfassen wir die wichtigsten molekularen Aspekte dieser Regulation zusammen und stellen diese in den größeren Zusammenhang von Training und Entzündung im Skelettmuskel.
SCHLÜSSELWÖRTER: Skelettmuskel, Training, Metabolismus, Entzündung, PGC-1α
Obesity, hypertension, cardiac diseases and other chronic pathologies have reached epidemic proportions in Western societies and are rising world-wide (20). A first line of treatment for most chronic diseases includes lifestyle-based interventions such a smoking cessation, decreased salt intake, a balanced diet and exercise. Surprisingly, despite the potent effect of physical activity on the prevention and treatment of many of these pathologies that in some cases rivals that of prescribed drugs, our knowledge of the molecular mechanisms that underlie the beneficial adaptations induced by exercise or pathological events in skeletal muscle remains rudimentary.
The etiologies of most chronic diseases closely correlate with a persistent, low-grade, sterile inflammation (19). Importantly, besides a systemic elevation of pro-inflammatory cytokine levels, increased immune cell infiltration and activation is observed in various organs (24). Macrophage activation in white adipose tissue and thereby increased secretion of pro-inflammatory cytokines and similar events in other peripheral organs such as liver and skeletal muscle contribute to the development of peripheral insulin resistance and other disorders (24). Thus, reversing inflammatory processes by exercise might reduce the pathological consequences of chronic diseases (10).
The molecular systems that are responsible for regulating metabolism and inflammation have co-evolved and strongly influence each other in a negative manner (21). For example, in skeletal muscle, induction of a pro-inflammatory program by the nuclear factor κB (NF-κB), a master regulator of inflammatory gene transcription, results in a repression of oxidative capacity while at the same time promoting fiber atrophy and muscle wasting, at least when activated in a prolonged manner (8). A mechanistic understanding of the mutual regulation between muscle metabolism and inflammation is therefore of eminent importance for the development of novel pharmacological approaches for many chronic diseases.
INFLAMMATION OF MUSCLE TISSUE IN HEALTH AND DISEASE
Inflammatory processes are important for physiological muscle function, in particular for adaptation to exercise. Bouts of contraction are linked to fiber damage, which initiate a highly orchestrated activation of different cell types instrumental for normal repair and regeneration post-exercise (4). In regular muscle regeneration, resident granulocytes and leukocytes are rapidly activated in muscle beds with contraction-mediated fiber damage. These cells sense fiber damage and release chemokines to activate and attract additional immune cells (4, 8). Moreover, the production and secretion of tumor necrosis factor α(TNFα), interleukin 6 (IL-6) and related cytokines establish a pro-inflammatory milieu. Subsequently, infiltrating macrophages complement the action of tissue-resident cells, and a classical, M1-type macrophage activation in this pro-inflammatory environment promotes debris removal. Later, the macrophage activation pattern shifts from the M1- to a M2-type in conjunction with the production of anti-inflammatory cytokines such as IL-10 and IL-4, indicating a transition from the clean-up to the repair and regeneration phase (31). In addition, activation of fibro/adipogenic progenitors (FAPs), pericytes, mesangioblasts, fibroblasts and epithelial cells contribute to muscle regeneration. Most importantly however, asymmetric proliferation and differentiation of satellite cells, the resident, lineage-committed muscle stem cells, triggered by various signals is instrumental for fiber repair and de novo fiber generation (5).
Besides the importance of orchestrated inflammation in muscle regeneration and exercise adaptation, unchecked inflammatory reactions are associated with a number of skeletal muscle-related pathologies, most directly in inflammatory myopathies or cachexia (23). Then, inflammation is a major contributor to the pathology in various muscular dystrophies, including Duchenne muscular dystrophy, which are characterized by a sustained pro-inflammatory environment and dramatically increased fibrosis (23). Finally, a persistent, sterile inflammation in muscle accompanies a number of chronic diseases, such as type 2 diabetes (25). The exact steps leading to peripheral insulin resistance are still incompletely understood. In muscle, activation of the toll-like receptors 4 (TLR4) by excessively elevated levels of circulating fatty acids however initiates a signaling cascade involving NF-κB-mediated expression and secretion of TNFα, IL-1βand other pro-inflammatory cytokines and chemokines (11).
THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ COACTIVATOR 1α (PGC-1α) IN SKELETAL MUSCLE
Adaptation of skeletal muscle to physical activity is a complex biological program that entails a massive change in the transcription rates of numerous genes. The peroxisome proliferator-activated receptor γcoactivator 1α(PGC-1α) has emerged as a potential regulatory nexus in the plastic changes of muscle fibers upon endurance exercise (27) (Fig. 1). PGC-1αintegrates various signaling pathways that are activated in a contracting muscle fiber and result in increased transcription of the PPARGC1A gene (which encodes PGC-1α) and posttranslational modifications of the PGC-1αprotein (15, 28). As a transcriptional co-activator, PGC-1αsubsequently interacts with numerous transcription factors in a temporally controlled manner to regulate a complex transcriptional program (3). In skeletal muscle, PGC-1α-controlled target gene expression collectively results in an endurance-trained muscle phenotype. Accordingly, transgenic overexpression of PGC-1αin mice leads to a contractile and metabolic shift towards oxidative, slow-twitch, high endurance muscle fibers (22). Importantly, activation of PGC-1αin skeletal muscle not only promotes most adaptations of muscle to endurance training, but also initiates changes in epithelial cells and hence tissue vascularization (1), the neuromuscular junction (2) and other non-muscle cell types (28).
Inversely, reduced muscle PGC-1αlevels have been associated with increased insulin resistance in human patients, at least in certain populations (19). Likewise, skeletal muscle-specific ablation of the PPARGC1A gene results in abnormal glucose and insulin homeostases in mice (17). Moreover, these mice exhibit a switch towards glycolytic muscle fibers, impaired endurance capacity and activity-dependent fiber damage (16). Hence, in many aspects, muscle-specific PGC-1αknockout animals resemble pathological inactivity in humans (13). Elevation of PGC-1αin muscle improves various muscle diseases, for example Duchenne muscular dystrophy (18) or sarcopenia (32), and, at least in combination with physical activity, ameliorates systemic glucose homeostasis (29). Therefore, pharmacological targeting of proteins up- and downstream of PGC-1αis one of the main strategy in the design of so-called “exercise mimetics”, small molecules that should elicit exercise-like effects in skeletal muscle (7). However, the feasibility of obtaining true exercise mimetics is still hotly debated (6).
AN ANTI-INFLAMMATORY ACTION OF EXERCISE AND PGC-1α
Physical activity is an efficient intervention to reduce the pathological, chronic, persistent inflammation observed in many patients (12) even though exercise and inflammation are linked in a complex manner (10) (Fig. 2). For example, extreme performance results in a massive inflammation and an ensuing temporary immune suppression (14). Surprisingly, even moderate training results in elevated levels of several cytokines and cytokine-like proteins (26, 28). These signaling molecules that can act in an auto-, para- and/or endocrine manner, have been termed myokines (26, 28), analogous to adipokines produces in adipose tissue. Intriguingly, the growing number of identified myokines includes factors that traditionally have been described as pro-inflammatory cytokines, e.g. the prototypical myokine IL-6. Thus, persistently elevated IL-6 levels have been associated with obesity and insulin resistance, but when released as a myokine, IL-6 mediates a number of beneficial effects (26). It is conceivable that these diametrically opposite effects are due to the very different secretion pattern of IL-6 in these two contexts, co-release of other factors or fundamental differences in IL-6 sensitivity in physiological compared to pathophysiological settings. However, the exact mechanisms are still unclear. In any case, the increase in plasma levels of immunomodulatory factors such as cortisol, growth hormone, epinephrine and others post-exercise favor an anti-inflammatory environment (12).
Based on its role as central regulator of exercise adaptation, it is not surprising that PGC-1αcontrols the expression of several myokines in the trained muscle fiber, e.g. irisin, meteorin-like, secreted phosphoprotein 1 (SPP1) or β-aminoisobutyric acid (BAIBA, a non-peptide myokine) (28). Meteorin-like and SPP1 induce changes in target tissues by activating eosinophils and macrophages, respectively. Thus, at least part of the exercise effect on inflammation is mediated by PGC-1α-controlled cellular cross-talk. In addition, PGC-1α also has a strong inhibitory role on pro-inflammatory gene expression in muscle, at least in part mediated by inhibition of activating phosphorylation events on the p65 subunit of the NF-κB transcription factor (9). Inversely, inflammation in most cases reduces the levels of PGC-1αin muscle, e.g. in the case of sepsis-induced muscle atrophy (8). Moreover, this inhibition is at least in part dependent on NF-κB, implying a mutually negative regulation of these two factors (8). Accordingly, the expression of TNFαand IL-6 in muscle both negatively correlate with PGC-1αlevels in normal, glucose intolerant and diabetic individuals (17). Therefore, the reciprocal regulation of PGC-1αand NF-κB conceivably is the molecular hinge in skeletal muscle that determines the balance between the anti-inflammatory, oxidative, trained environment in health and the pro-inflammatory, atrophic, insulin resistant conditions in disease (Fig. 3).
Inflammation, muscle metabolism and function are intrinsically linked and determine the health status of this organ, in many cases even systemic well-being. The complex interplay between these systems is underlined by shared mediators, in particular pro-inflammatory cytokines that in different contexts also can act as beneficial myokines mediating systemic exercise effects. On the molecular level, the co-activator PGC-1αand the transcription factor NF-κB seem central in balancing physiological and pathophysiological states. Even though pharmacological activators of PGC-1αthat can be applied in a chronic and safe manner remain elusive (30), a better understanding of the mutual regulation between these two factors will hopefully lead to the identification of novel therapeutic targets and thereby new prevention and treatment modalities not only for many skeletal muscle disorders, but also a number of other chronic diseases. In the meantime, exercise remains the most efficient manner to safely increase muscle PGC-1αand reduce the risk for such pathologies.
The projects in our group are funded by the ERC Consolidator grant 616830-MUSCLE_NET, the Swiss National Science Foundation, SystemsX.ch, the Swiss Society for Research on Muscle Diseases (SSEM), the Neuromuscular Research Association Basel (NeRAB), the Gebert-Rüf Foundation “Rare Diseases” Program, the “Novartis Stiftung für medizinisch-biologische Forschung”, the University of Basel and the Biozentrum. The funders had no role in the preparation of the manuscript.
Conflict of Interest
The authors have no conflict of interest.
- HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 2008; 451: 1008-1012.
- Morphological and functional remodelling of the neuromuscular junction by skeletal muscle PGC-1alpha. Nat Commun. 2014; 5: 3569.
- Transcriptional network analysis in muscle reveals AP-1 as a partner of PGC-1alpha in the regulation of the hypoxic gene program. Mol Cell Biol. 2014; 34: 2996-3012.
- Cellular dynamics in the muscle satellite cell niche. EMBO Rep. 2013; 14:1062-1072.
- The emerging biology of muscle stem cells: implications for cellbasedtherapies. Bioessays. 2013; 35: 231-241.
- Lack of adequate appreciation of physical exercise‘s complexities can pre-empt appropriate design and interpretation in scientific discovery. J Physiol. 2009; 587: 5527-5539.
- Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with ‚exercise mimetics‘. Diabetologia. 2009; 52: 2015-2026.
- Functional crosstalk of PGC-1 coactivators and inflammation in skeletal musclepathophysiology. Semin Immunopathol. 2014; 36: 27-53.
- The peroxisome proliferator-activated receptor gamma coactivator1alpha/beta (PGC-1) coactivators repress the transcriptional activity of NF-kappaB in skeletal muscle cells. J Biol Chem. 2013; 288: 2246-2260.
- Exercise and inflammation. J Appl Physiol. 2007; 103: 376-377.
- Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 2012; 15: 635-645.
- Immune function in sport and exercise. J Appl Physiol. 2007; 103: 693-699.
- The biology of PGC-1alpha and its therapeutic potential. Trends Pharmacol Sci. 2009; 30: 322-329.
- Peroxisome proliferator-activated receptor-gamma coactivator-1alpha in muscle links metabolism to inflammation. Clin Exp Pharmacol Physiol. 2009; 36: 1139-1143.
- Regulation of skeletal muscle cell plasticity by the peroxisome proliferator-activated receptor gamma coactivator 1alpha. J Recept Signal Transduct Res. 2010; 30: 376-384.
- Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha musclespecific knock-out animals. J Biol Chem. 2007; 282: 30014-30021.
- Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. J Clin Invest. 2007; 117: 3463-3474.
- PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev. 2007; 21: 770-783.
- The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008; 454: 463-469.
- Obesity and diabetes in the developing world--a growing challenge. N Engl J Med. 2007; 356: 213-215.
- Inflammation and metabolic disorders. Nature. 2006; 444: 860-867.
- Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature. 2002; 418: 797-801.
- NF-kappaB signaling in skeletal muscle: prospects for intervention in muscle diseases. J Mol Med. 2008; 86: 747-759.
- Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010; 72: 219-246.
- The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012; 18: 363-374.
- Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012; 8: 457-465.
- New insights in the regulation of skeletal muscle PGC-1α by exercise and metabolic diseases. Drug Discov Today Dis Models. 2013; 10: e79-e85.
- Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone. 2015; 80: 115-25.
- PGC-1alpha improves glucose homeostasis in skeletal muscle in an activity-dependent manner. Diabetes. 2013; 62: 85-95.
- Modulation of PGC-1alpha activity as a treatment for metabolic and muscle-related diseases. Drug Discov Today. 2014; 19: 1024-1029.
- Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol. 2010; 298: R1173-R1187.
- Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci USA. 2009; 106: 20405-20410.
Biozentrum, University of Basel
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