Novel Target Genes for Catecholamines in Skeletal Muscle

Peter Arner

Department of Medicine, Karolinska Institutet, SE-141 86 Stockholm, Sweden

Address all correspondence and requests for reprints to: Prof. Peter Arner, M.D., Center for Metabolism and Endocrinology, M63, Karolinska University Hospital-Huddinge, SE-141 86 Stockholm, Sweden. E-mail: peter.arner{at}medhs.ki.se.

Few hormones have been studied more intensely than catecholamines, and their diverse roles in body function are well recognized. The complex action of catecholamine is perhaps most evident in skeletal muscle. Here, the hormones have catabolic effects, which lead to mobilization of energy through breakdown of glycogen and lipids. Catecholamines also increase muscle contraction and blood flow. Furthermore, the hormones have anabolic effects because they stimulate protein synthesis, inhibit protein breakdown, and cause muscle hypertrophy. Some actions are rapid (i.e. catabolic effects, muscle contraction, vascular reactivity) and are regulated by signaling through G protein-coupled receptors. The anabolic effects have a slower onset and involve regulation of gene expression. Relatively little is known about catecholamine-regulated genes, and most studies have been performed in cell cultures or using animal models. From a clinical point of view, human in vivo studies are warranted because they might recognize important species differences. Furthermore, the complex gene-environment interactions that take place in humans are hard to mimic in animal models.

Microarrays are powerful tools for global analysis of gene expression and protein content of cells or tissues, and they open new windows in physiological and pathophysiological processes (1, 2, 3). Several commercial and public systems are available. Robust computer programs are at hand for statistical treatment of data or functional analysis of the gene expression results, such as clustering of genes into functional groups and pathway analyses.

In this issue of JCEM, Viguerie et al. (4) have used global cDNA array technology to detect in vivo changes in gene expression of human skeletal muscle after iv epinephrine infusion. Only about 4% of the approximately 40,000 genes on the microarray chips were up- or down-regulated by the catecholamine. This low level of regulation is, on the other hand, often observed in human studies. For example, Rome et al. (5) infused insulin iv and investigated approximately 30,000 genes in human skeletal muscle by cDNA microarray. Although control of gene expression by insulin is recognized as a major effect of the hormone, only approximately 3% of the genes investigated were regulated in skeletal muscle during the hyperinsulinemic clamp. The magnitude of skeletal muscle gene response to epinephrine was small. Most genes showed less than a 50% decrease or less than a 100% increase in expression, although the hormone was infused for 6 h (4). This is different from in vivo changes induced by insulin (5) or T3 (6). These hormones appear to have a much stronger effect in vivo on the level of gene expression in human skeletal muscle than epinephrine.

In skeletal muscle, catecholamines act mainly through the Gs protein-coupled ß2 adrenoceptors and stimulate cAMP production. cAMP is an important modulator of gene transcription (7). Therefore, it is expected that catecholamine stimulation influences the expression of skeletal muscle genes that are transcriptionally regulated by cAMP. Indeed, many of the genes in human skeletal muscle that were found to be regulated after in vivo infusion of epinephrine were cAMP sensitive, such as the cAMP response element-binding protein family and related genes (mainly increased expression). A closer look into gene pathways in skeletal muscle reveals that epinephrine regulates a number of genes involved in signaling through the Gs-coupled receptor pathway (also cAMP dependent) as well as several of the enzymes in carbohydrate metabolism (about 30). This could mean that catecholamines have both long-term and short-term effects on the metabolism of glucose in skeletal muscle. The rapid ones activate the ß2-adrenoceptor signaling pathway (i.e. coupling, accumulation of cAMP, and phosphorylation of the protein kinase-A complex and enzymes). The long-term effects regulate the available amounts of signaling proteins and target enzymes in carbohydrate metabolism. Catecholamines also regulate several genes that are involved in lipid metabolism in human skeletal muscle. However, only a few genes, which are involved in mitochondrial respiratory chain, are altered by epinephrine infusion (4). Taken together, these findings support the notion that the major effect of catecholamines on metabolic rate in skeletal muscle is to supply to available mitochondrias substrates for oxidation.

Perhaps the most interesting observation in the study of Viguerie et al. (4) is that epinephrine has a significant effect on immunity and inflammatory responses in human skeletal muscle. There was a coordinate up-regulation of several chemokines with Cys-Cys motifs. These chemokines are involved in inflammatory and immunology processes. They are also chemotactic factors for inflammatory cells. Furthermore, a number of cytokines, cytokine receptors, and complement factors in human skeletal muscle were regulated in vivo by epinephrine.

At present, it is too early to say whether changes in skeletal muscle gene expression are just experimental observations or represent important physiological and pathophysiological events. Studies of gene expression must be validated by investigations of the corresponding proteins before any final conclusions can be drawn. However, many of the genes involved in inflammatory and immune responses, which were regulated by epinephrine, are secretory proteins. It is of interest to note that several cytokines, chemokines, and complement factors are secreted by human myoblasts in vitro (1, 8, 9) or by intact human muscle in vivo (10). Many of the corresponding genes were regulated by epinephrine infusion (4). The observations that myocytes have a protein secretory capacity could mean that skeletal muscle is a mediator of inflammatory or immune processes in other organs. Further support for this notion is that insulin also regulates the expression of inflammatory genes in human skeletal muscle (5). It is intriguing that the major hormones in control of energy processes in skeletal muscle also may regulate the putative inflammatory function of this tissue.

One could also speculate that catecholamines are involved in local inflammatory processes. An immune/inflammatory response could be important for muscle damage after excessive physical training (11). Muscle wasting in cachexia is believed to be caused by immune and inflammatory reactions (12); this could involve stress factors such as adrenergic hyperactivity in skeletal muscle. Finally, idiopathic inflammatory myopathies could at least in part be attributed to stress hormone reactions. For example, several of the genes in skeletal muscle that are regulated by epinephrine infusion are involved in a possible cross-talk between inflammatory cells that are recruited from the blood stream and human muscle cells (13). Interestingly, in an animal model of Duchenne muscular dystrophy there is up-regulation of several of the cytokines, chemokines, and cytokine receptors that were up-regulated by epinephrine in human skeletal muscle (4, 14).

The idea of a role of the adrenergic system in inflammation and immune response is not new. Animal studies suggest that norepinephrine could act as an endogenous immunomodulator in the brain (15). However, important human evidence is lacking so far, and, if anything, catecholamines may have quite different effects on inflammatory genes in brain compared with skeletal muscle. Norepinephrine reduces cytokine gene expression in brain cells, but the opposite is true in human skeletal muscle (4, 15).

The role of catecholamines in the regulation of immune response of antigen-presenting cells such as monocytes, macrophages, dendritic cells, and so-called helper lymphocytes is well recognized (15). However, the pattern of immune response of these cells to norepinephrine stimulation is clearly different from that seen after epinephrine stimulation of skeletal muscle. Catecholamines inhibit the production of proinflammatory cytokines and stimulate the production of antiinflammatory cytokines in immunocompetent cells (16). Only up-regulation of cytokines by epinephrine was observed in skeletal muscle (4). However, the skeletal muscle data should be interpreted with some caution because intact muscle tissue, which may contain circulatory immunocompetent cells, was investigated. Indeed, several of the genes regulated by epinephrine in skeletal muscle are highly expressed in leukocytes and tissues producing lymphocytes (4).

What are the key genes involved in catecholamineregulated inflammatory and immune processes of skeletal muscle? Many questions remain unanswered at this stage. Are they confined to a particular pathway or a specific cluster of genes? Do they provide inflammatory or immune signals to other organs as circulatory proteins, or do they just act on local events within the myocytes? Do they convey cross-talk between the myocytes and surrounded immunocompetent cells? Are the effects of other stress hormones (i.e. corticosteroids) the same or not? Further studies answering these questions may help us to understand the novel putative role of catecholamines in skeletal muscle, namely to serve as regulators of immune and inflammatory processes.

Received February 26, 2004.

Accepted February 26, 2004.

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