STZ-induced skeletal muscle atrophy is associated with increased p65 content and downregulation of insulin pathway without NF-κB canonical cascade activation.
Type 1 diabetes mellitus (DM)-induced skeletal muscle atrophy is associated with an increased incidence in morbidity and mortality. Although the precise mechanism of diabetes-induced skeletal muscle atrophy remains to be established, several NF-κB-dependent pro-inflammatory genes have been identified as potential therapeutic targets. Moreover, activation of NF-κB has previously been shown to be required for cytokine-induced loss of skeletal muscle proteins. Therefore, we investigated activation of the NF-κB canonical pathway, concomitant to insulin signaling activation in skeletal muscle from diabetes-induced rats. Ten rats injected with streptozotocin (STZ) 4 weeks prior to tissue extraction were compared to 10 control rats. Using total, cytosolic and nuclear protein extracts from hindlimb muscles: soleus (SOL), extensor digitorum longus (EDL), gastrocnemius (GM) and liver tissue, we assessed key proteins important for the activation of both NF-κB and insulin pathways. Insulin blood concentration decreased to 3.9 ± 1.2 mU/ml following STZ-injection resulting in hyperglycemia (17.9 ± 0.7 mmol/l). SOL, EDL and GM mass decreased, and liver mass increased following STZ injection. NF-κB/p65 content in SOL, GM and liver increased in STZ-injected rats, without any change in IκB degradation or IKK phosphorylation. Muscle NF-κB/p65 remained bound to IκB and did not translocate or bind to DNA. Although the canonical NF-κB cascade was not activated, STZ induced a decrease in insulin pathway proteins including insulin receptor (IR) and substrate (IRS-1) content and phosphorylation compared to control animals. A downregulation of insulin pathway proteins and muscle atrophy occurred in response to STZ administration, and despite increased p65 content, STZ treatment did not activate the canonical NF-κB cascade. Therefore, it is unlikely that hyperglycemia initiates skeletal muscle atrophy via activation of the NF-κB canonical pathway.
Kelleher
Andrew R
AR
Department of Exercise Science, Syracuse University, NY 13206, USA.
Fairchild
Timothy J
TJ
Keslacy
Stefan
S
D000818:Animals; D004247:DNA / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D051996:Transcription Factor RelA / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D007328:Insulin; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D013311:Streptozocin; D004247:DNA