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Effects of pharmacologic sclerostin inhibition or testosterone administration on soleus muscle atrophy in rodents after spinal cord injury.

Title: Effects of pharmacologic sclerostin inhibition or testosterone administration on soleus muscle atrophy in rodents after spinal cord injury.
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Name(s): Phillips, Ean G, author
Beggs, Luke A, author
Ye, Fan, author
Conover, Christine F, author
Beck, Darren T, author
Otzel, Dana M, author
Ghosh, Payal, author
Bassit, Anna C F, author
Borst, Stephen E, author
Yarrow, Joshua F, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2018-03-26
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Sclerostin is a circulating osteocyte-derived glycoprotein that negatively regulates Wnt-signaling after binding the LRP5/LRP6 co-receptors. Pharmacologic sclerostin inhibition produces bone anabolic effects after spinal cord injury (SCI), however, the effects of sclerostin-antibody (Scl-Ab) on muscle morphology remain unknown. In comparison, androgen administration produces bone antiresorptive effects after SCI and some, but not all, studies have reported that testosterone treatment ameliorates skeletal muscle atrophy in this context. Our purposes were to determine whether Scl-Ab prevents hindlimb muscle loss after SCI and compare the effects of Scl-Ab to testosterone enanthate (TE), an agent with known myotrophic effects. Male Sprague-Dawley rats aged 5 months received: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe contusion SCI, (C) SCI+TE (7.0 mg/wk, im), or (D) SCI+Scl-Ab (25 mg/kg, twice weekly, sc). Twenty-one days post-injury, SCI animals exhibited a 31% lower soleus mass in comparison to SHAM, accompanied by >50% lower soleus muscle fiber cross-sectional area (fCSA) (p<0.01 for all fiber types). Scl-Ab did not prevent soleus atrophy, consistent with the relatively low circulating sclerostin concentrations and with the 91-99% lower LRP5/LRP6 gene expressions in soleus versus tibia (p<0.001), a tissue with known anabolic responsiveness to Scl-Ab. In comparison, TE partially prevented soleus atrophy and increased levator ani/bulbocavernosus (LABC) mass by 30-40% (p<0.001 vs all groups). The differing myotrophic responsiveness coincided with a 3-fold higher androgen receptor gene expression in LABC versus soleus (p<0.01). This study provides the first direct evidence that Scl-Ab does not prevent soleus muscle atrophy in rodents after SCI and suggests that variable myotrophic responses in rodent muscles after androgen administration are influenced by androgen receptor expression.
Identifier: FSU_pmch_29579075 (IID), 10.1371/journal.pone.0194440 (DOI), PMC5868788 (PMCID), 29579075 (RID), 29579075 (EID), PONE-D-17-24505 (PII)
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868788.
Subject(s): Animals
Antibodies, Neutralizing/pharmacology
Bone Morphogenetic Proteins/antagonists & inhibitors
Bone Morphogenetic Proteins/metabolism
Genetic Markers
Male
Muscle, Skeletal/metabolism
Muscle, Skeletal/pathology
Muscular Atrophy/drug therapy
Muscular Atrophy/etiology
Muscular Atrophy/metabolism
Muscular Atrophy/pathology
Rats
Rats, Sprague-Dawley
Receptors, Androgen/metabolism
Spinal Cord Injuries/complications
Spinal Cord Injuries/drug therapy
Spinal Cord Injuries/metabolism
Spinal Cord Injuries/pathology
Testosterone/pharmacology
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_29579075
Host Institution: FSU
Is Part Of: PloS one.
1932-6203
Issue: iss. 3, vol. 13

Choose the citation style.
Phillips, E. G., Beggs, L. A., Ye, F., Conover, C. F., Beck, D. T., Otzel, D. M., … Yarrow, J. F. (2018). Effects of pharmacologic sclerostin inhibition or testosterone administration on soleus muscle atrophy in rodents after spinal cord injury. Plos One. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_29579075