Nitric oxide production is a proximal signaling event controlling exercise-induced mRNA expression in human skeletal muscle.
Previous studies have described the magnitude and time course by which several genes are regulated within exercising skeletal muscle. These include interleukin-6 (IL-6), interleukin-8 (IL-8), heme oxygenase-1 (HO-1), and heat shock protein-72 (HSP72), which are involved in secondary signaling and preservation of intracellular environment. However, the primary signaling mechanisms coupling contraction to transcription are unknown. We hypothesized that exercise-induced nitric oxide (NO) production is an important signaling event for IL-6, IL-8, HO-1, and HSP72 expression in muscle. Twenty healthy males participated in the study. By real-time PCR, mRNA levels for 11 genes were determined in thigh muscle biopsies obtained 1) before and after 2 h knee extensor exercise without (control) and with concomitant NO synthase inhibition (nitro-L-arginine methyl ester, L-NAME, 5 mg x kg(-1)); or 2) before and after 2 h femoral artery infusion of the NO donor nitroglycerin (NTG, 1.5 microg x kg(-1) x min(-1)). L-NAME caused marked reductions in exercise-induced expression of 4 of 11 mRNAs including IL-6, IL-8, and HO-1. IL-6 protein release from the study leg to the circulation increased in the control but not in the L-NAME trial. NTG infusion significantly augmented expression of the mRNAs attenuated by L-NAME. These findings advance the novel concept that NO production contributes to regulation of gene expression in muscle during exercise. Subsequently, we sought evidence for involvement of AMP-activated kinase or nuclear factor kappa B, but found none.
Steensberg
Adam
A
Centre of Inflammation and Metabolism, Department of Infectious Diseases, National Hospital, Copenhagen O, Denmark.
Keller
Charlotte
C
Hillig
Thore
T
Frøsig
Christian
C
Wojtaszewski
Jørgen F P
JF
Pedersen
Bente Klarlund
BK
Pilegaard
Henriette
H
Sander
Mikael
M
D055372:AMP-Activated Protein Kinases; D000328:Adult; D001706:Biopsy; D004789:Enzyme Activation; D015444:Exercise / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013848:Thigh
D015850:Interleukin-6; D016209:Interleukin-8; D009097:Multienzyme Complexes; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D019331:NG-Nitroarginine Methyl Ester