PMID- 31614775 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20211029 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 11 IP - 10 DP - 2019 Oct 12 TI - Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice. LID - 10.3390/cancers11101541 [doi] LID - 1541 AB - Physical activity improves the prognosis of cancer patients, partly by contrasting the associated muscle wasting (cachexia), through still unknown mechanisms. We asked whether aerobic exercise causes secretion by skeletal muscles of proteins (myokines) that may contrast cachexia. Media conditioned by peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha)-expressing myotubes, reproducing some metabolic adaptations of aerobic exercise, as increased mitochondrial biogenesis and oxidative phosphorylation, restrained constitutively active Forkhead box-containing subfamily O3 (caFoxO3)-induced proteolysis. Microarray analysis identified amphiregulin (AREG), natriuretic peptide precursor B (NppB), musclin and fibroblast growth factor 18 (FGF18) as myokines highly induced by PGC1alpha. Notably, only musclin tended to be low in muscle of mice with a rare human renal carcinoma; it was reduced in plasma and in muscles of C26-bearing mice and in atrophying myotubes, where PGC1alpha expression is impaired. Therefore, we electroporated the Tibialis Anterior (TA) of C26-bearing mice with musclin or (its receptor) natriuretic peptide receptor 3 (Npr3)-encoding plasmids and found a preserved fiber area, as a result of restrained proteolysis. Musclin knockout (KO) mice lose more muscle tissue during growth of two distinct cachexia-causing tumors. Running protected C26-bearing mice from cachexia, not changing tumor growth, and rescued the C26-induced downregulation of musclin in muscles and plasma. Musclin expression did not change in overloaded plantaris of mice, recapitulating partially muscle adaptations to anaerobic exercise. Musclin might, therefore, be beneficial to cancer patients who cannot exercise and are at risk of cachexia and may help to explain how aerobic exercise alleviates cancer-induced muscle wasting. FAU - Re Cecconi, Andrea D AU - Re Cecconi AD AUID- ORCID: 0000-0003-1502-9108 AD - Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy. andrea.rececconi@marionegri.it. FAU - Forti, Mara AU - Forti M AD - Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy. mara.forti@guest.marionegri.it. FAU - Chiappa, Michela AU - Chiappa M AD - Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy. michela.chiappa@marionegri.it. FAU - Zhu, Zhiyong AU - Zhu Z AD - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. zhiyong-zhu@uiowa.edu. AD - Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. zhiyong-zhu@uiowa.edu. AD - Department of Medicine, Medical Center, Department of Veterans Affairs, Iowa City, IA 52246, USA. zhiyong-zhu@uiowa.edu. FAU - Zingman, Leonid V AU - Zingman LV AD - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. leonid-zingman@uiowa.edu. AD - Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. leonid-zingman@uiowa.edu. AD - Department of Medicine, Medical Center, Department of Veterans Affairs, Iowa City, IA 52246, USA. leonid-zingman@uiowa.edu. FAU - Cervo, Luigi AU - Cervo L AD - Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy. luigi.cervo@marionegri.it. FAU - Beltrame, Luca AU - Beltrame L AUID- ORCID: 0000-0003-3631-6544 AD - Department of Oncology, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy. luca.beltrame@marionegri.it. FAU - Marchini, Sergio AU - Marchini S AD - Department of Oncology, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy. sergio.marchini@marionegri.it. FAU - Piccirillo, Rosanna AU - Piccirillo R AUID- ORCID: 0000-0002-1613-9352 AD - Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy. rosanna.piccirillo@marionegri.it. LA - eng GR - I01 BX004840/BX/BLRD VA/United States GR - 2014-1164/Fondazione Cariplo/ GR - 11423/Associazione Italiana per la Ricerca sul Cancro/ PT - Journal Article DEP - 20191012 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC6826436 OTO - NOTNLM OT - PGC1alpha OT - aerobic exercise OT - cancer cachexia OT - muscle atrophy OT - muscle wasting OT - musclin OT - myokine COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2019/10/17 06:00 MHDA- 2019/10/17 06:01 PMCR- 2019/10/12 CRDT- 2019/10/17 06:00 PHST- 2019/06/07 00:00 [received] PHST- 2019/09/20 00:00 [revised] PHST- 2019/10/09 00:00 [accepted] PHST- 2019/10/17 06:00 [entrez] PHST- 2019/10/17 06:00 [pubmed] PHST- 2019/10/17 06:01 [medline] PHST- 2019/10/12 00:00 [pmc-release] AID - cancers11101541 [pii] AID - cancers-11-01541 [pii] AID - 10.3390/cancers11101541 [doi] PST - epublish SO - Cancers (Basel). 2019 Oct 12;11(10):1541. doi: 10.3390/cancers11101541.