IL-6 and epinephrine have divergent fiber type effects on intramuscular lipolysis

IL-6 is an exercise-regulated myokine that has been suggested to increase lipolysis in fast-twitch skeletal muscle. However, it is not known if a similar effect is present in slow-twitch muscle. Furthermore, epinephrine increases IL-6 secretion from skeletal muscle, suggesting that IL-6 could play a role in mediating the lipolytic effects of catecholamines. The purpose of this study was to determine whether IL-6 stimulates skeletal muscle lipolysis in a fiber type dependent manner and is required for epinephrine-stimulated lipolysis in murine skeletal muscle. Soleus and extensor digitorum longus (EDL) muscles from male C57BL/6J wild-type and IL-6(-/-) mice were incubated with 1 μM (183 ng/ml) epinephrine or 75 ng/ml recombinant IL-6 (rIL-6) for 60 min. IL-6 treatment increased 5'-AMP-activated protein kinase and signal transducer and activator of transcription 3 phosphorylation and glycerol release in isolated EDL but not soleus muscles from C57BL/6J mice. Conversely, epinephrine increased glycerol release in soleus but not EDL muscles from C57BL/6J mice. Basal lipolysis was elevated in soleus muscle from IL-6(-/-) mice, and this was associated with increases in adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58). The increase in ATGL content does not appear to be due to a loss of IL-6's direct effects, because ex vivo treatment with IL-6 failed to alter the expression of ATGL mRNA in soleus muscle. In summary, IL-6 stimulates lipolysis in glycolytic but not oxidative muscle, whereas the opposite fiber type effect is seen with epinephrine. The absence of IL-6 indirectly upregulates lipolysis, and this is associated with increases in ATGL and its coactivator CGI-58.