PMID- 33527776 OWN - NLM STAT- MEDLINE DCOM- 20211028 LR - 20240504 IS - 2190-6009 (Electronic) IS - 2190-5991 (Print) IS - 2190-5991 (Linking) VI - 12 IP - 2 DP - 2021 Apr TI - FoxP1 is a transcriptional repressor associated with cancer cachexia that induces skeletal muscle wasting and weakness. PG - 421-442 LID - 10.1002/jcsm.12666 [doi] AB - BACKGROUND: Skeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein, we investigated the biological significance of Forkhead box P1 (FoxP1), a transcriptional repressor that we demonstrate is up-regulated in skeletal muscle in multiple models of cancer cachexia and in cachectic cancer patients. METHODS: Inducible, skeletal muscle-specific FoxP1 over-expressing (FoxP1(iSkmTg/Tg) ) mice were generated through crossing conditional Foxp1a transgenic mice with HSA-MCM mice that express tamoxifen-inducible Cre recombinase under control of the skeletal muscle actin promoter. To determine the requirement of FoxP1 for cancer-induced skeletal muscle wasting, FoxP1-shRNA was packaged and targeted to muscles using AAV9 delivery prior to inoculation of mice with Colon-26 Adenocarcinoma (C26) cells. RESULTS: Up-regulation of FoxP1 in adult skeletal muscle was sufficient to induce features of cachexia, including 15% reduction in body mass (P < 0.05), and a 16-27% reduction in skeletal muscle mass (P < 0.05) that was characterized by a 20% reduction in muscle fibre cross-sectional area of type IIX/B muscle fibres (P = 0.020). Skeletal muscles from FoxP1(iSkmTg/Tg) mice also showed significant damage and myopathy characterized by the presence of centrally nucleated myofibres, extracellular matrix expansion, and were 19-26% weaker than controls (P < 0.05). Transcriptomic analysis revealed FoxP1 as a potent transcriptional repressor of skeletal muscle gene expression, with enrichment of pathways related to skeletal muscle structure and function, growth signalling, and cell quality control. Because FoxP1 functions, at least in part, as a transcriptional repressor through its interaction with histone deacetylase proteins, we treated FoxP1(iSkmTg/Tg) mice with Trichostatin A, and found that this completely prevented the loss of muscle mass (p = 0.007) and fibre atrophy (P < 0.001) in the tibialis anterior. In the context of cancer, FoxP1 knockdown blocked the cancer-induced repression of myocyte enhancer factor 2 (MEF2)-target genes critical to muscle differentiation and repair, improved muscle ultrastructure, and attenuated muscle fibre atrophy by 50% (P < 0.05). CONCLUSIONS: In summary, we identify FoxP1 as a novel repressor of skeletal muscle gene expression that is increased in cancer cachexia, whose up-regulation is sufficient to induce skeletal muscle wasting and weakness, and required for the normal wasting response to cancer. CI - (c) 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders. FAU - Neyroud, Daria AU - Neyroud D AUID- ORCID: 0000-0001-5886-802X AD - Department of Physical Therapy, University of Florida, Gainesville, FL, USA. FAU - Nosacka, Rachel L AU - Nosacka RL AUID- ORCID: 0000-0001-8347-9501 AD - Department of Physical Therapy, University of Florida, Gainesville, FL, USA. FAU - Callaway, Chandler S AU - Callaway CS AUID- ORCID: 0000-0002-4562-0508 AD - Department of Physical Therapy, University of Florida, Gainesville, FL, USA. FAU - Trevino, Jose G AU - Trevino JG AD - Department of Surgery, University of Florida, Gainesville, FL, USA. FAU - Hu, Hui AU - Hu H AD - Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Judge, Sarah M AU - Judge SM AUID- ORCID: 0000-0002-3974-0247 AD - Department of Physical Therapy, University of Florida, Gainesville, FL, USA. FAU - Judge, Andrew R AU - Judge AR AUID- ORCID: 0000-0002-4488-291X AD - Department of Physical Therapy, University of Florida, Gainesville, FL, USA. LA - eng GR - R01 AR060209/AR/NIAMS NIH HHS/United States GR - T32 HD043730/HD/NICHD NIH HHS/United States GR - U54 AR052646/AR/NIAMS NIH HHS/United States GR - UL1 TR001430/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210201 PL - Germany TA - J Cachexia Sarcopenia Muscle JT - Journal of cachexia, sarcopenia and muscle JID - 101552883 RN - 0 (FOXP1 protein, human) RN - 0 (Forkhead Transcription Factors) RN - 0 (Foxp1 protein, mouse) RN - 0 (Repressor Proteins) SB - IM MH - Animals MH - *Cachexia/etiology/genetics/pathology MH - *Colonic Neoplasms/complications/genetics/pathology MH - Forkhead Transcription Factors/genetics MH - Humans MH - Mice MH - Muscle, Skeletal/pathology MH - Muscular Atrophy/genetics/pathology MH - Repressor Proteins/genetics PMC - PMC8061399 OTO - NOTNLM OT - Cancer cachexia OT - Muscle atrophy OT - Muscle regeneration OT - Muscle weakness OT - Pancreatic cancer COIS- The authors declare that they have no conflict of interest. EDAT- 2021/02/03 06:00 MHDA- 2021/10/29 06:00 PMCR- 2021/04/01 CRDT- 2021/02/02 06:22 PHST- 2020/12/05 00:00 [revised] PHST- 2020/08/05 00:00 [received] PHST- 2020/12/16 00:00 [accepted] PHST- 2021/02/03 06:00 [pubmed] PHST- 2021/10/29 06:00 [medline] PHST- 2021/02/02 06:22 [entrez] PHST- 2021/04/01 00:00 [pmc-release] AID - JCSM12666 [pii] AID - 10.1002/jcsm.12666 [doi] PST - ppublish SO - J Cachexia Sarcopenia Muscle. 2021 Apr;12(2):421-442. doi: 10.1002/jcsm.12666. Epub 2021 Feb 1.