title: Musclin is an activity-stimulated myokine that enhances physical endurance.
abstract: Exercise remains the most effective way to promote physical and metabolic wellbeing, but molecular mechanisms underlying exercise tolerance and its plasticity are only partially understood. In this study we identify musclin-a peptide with high homology to natriuretic peptides (NP)-as an exercise-responsive myokine that acts to enhance exercise capacity in mice. We use human primary myoblast culture and in vivo murine models to establish that the activity-related production of musclin is driven by Ca(2+)-dependent activation of Akt1 and the release of musclin-encoding gene (Ostn) transcription from forkhead box O1 transcription factor inhibition. Disruption of Ostn and elimination of musclin secretion in mice results in reduced exercise tolerance that can be rescued by treatment with recombinant musclin. Reduced exercise capacity in mice with disrupted musclin signaling is associated with a trend toward lower levels of plasma atrial NP (ANP) and significantly smaller levels of cyclic guanosine monophosphate (cGMP) and peroxisome proliferator-activated receptor gamma coactivator 1-α in skeletal muscles after exposure to exercise. Furthermore, in agreement with the established musclin ability to interact with NP clearance receptors, but not with NP guanyl cyclase-coupled signaling receptors, we demonstrate that musclin enhances cGMP production in cultured myoblasts only when applied together with ANP. Elimination of the activity-related musclin-dependent boost of ANP/cGMP signaling results in significantly lower maximum aerobic capacity, mitochondrial protein content, respiratory complex protein expression, and succinate dehydrogenase activity in skeletal muscles. Together, these data indicate that musclin enhances physical endurance by promoting mitochondrial biogenesis.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Subbotina
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Ana
authors.initials: A
authors.lastname: Sierra
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Siva Rama Krishna
authors.initials: SR
authors.lastname: Koganti
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905;
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stepniak
authors.affiliation: Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Susan A
authors.initials: SA
authors.lastname: Walsh
authors.affiliation: Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Michael R
authors.initials: MR
authors.lastname: Acevedo
authors.affiliation: Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905;
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Perez-Terzic
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242; leonid-zingman@uiowa.edu denice-zingman@uiowa.edu.
authors.forename: Denice M
authors.initials: DM
authors.lastname: Hodgson-Zingman
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Department of Medicine, Medical Center, Department of Veterans Affairs, Iowa City, IA 52242 leonid-zingman@uiowa.edu denice-zingman@uiowa.edu.
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Zingman
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015153:Blotting, Western; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D061207:Calcium Ionophores / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D061207:Calcium Ionophores; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009124:Muscle Proteins; C498449:Ostn protein, mouse; D014157:Transcription Factors; D000001:Calcimycin; D009320:Atrial Natriuretic Factor; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP; D002118:Calcium
keywords: exercise; mitochondria; natriuretic peptide; osteocrin; skeletal muscle