Chronic doxorubicin administration impacts satellite cell and capillary abundance in a muscle-specific manner

Andrew C. D'Lugos, Christopher S. Fry, Jordan C. Ormsby, Kaylin R. Sweeney, Camille R. Brightwell, Taben Hale, Rayna J Gonzales, Siddhartha S. Angadi, Chad C. Carroll, Jared M. Dickinson

Research output: Contribution to journalArticle

Abstract

Anthracycline chemotherapies are effective at reducing disease recurrence and mortality in cancer patients. However, these drugs also contribute to skeletal muscle wasting and dysfunction. The purpose of this study was to assess the impact of chronic doxorubicin (DOX) administration on satellite cell and capillary densities in different skeletal muscles. We hypothesized that DOX would reduce satellite cell and capillary densities of the soleus (SOL) and extensor digitorum longus (EDL) muscles, along with muscle fiber size. Ovariectomized female Sprague-Dawley rats were randomized to receive three bi-weekly intraperitoneal injections of DOX (4 mg∙kg-1 ; cumulative dose 12 mg∙kg-1 ) or vehicle (VEH; saline). Animals were euthanized 5d following the last injection and the SOL and EDL were dissected and prepared for immunohistochemical and RT-qPCR analyses. Relative to VEH, CSA of the SOL and EDL fibers were 26% and 33% smaller, respectively, in DOX (P < 0.05). In the SOL, satellite cell and capillary densities were 39% and 35% lower, respectively, in DOX (P < 0.05), whereas in the EDL satellite cell and capillary densities were unaffected by DOX administration (P > 0.05). Proliferating satellite cells were unaffected by DOX in the SOL (P > 0.05). In the SOL, MYF5 mRNA expression was increased in DOX (P < 0.05), while in the EDL MGF mRNA expression was reduced in DOX (P < 0.05). Chronic DOX administration is associated with reduced fiber size in the SOL and EDL; however, DOX appeared to reduce satellite cell and capillary densities only in the SOL. These findings highlight that therapeutic targets to protect skeletal muscle from DOX may vary across muscles.

Original languageEnglish (US)
Pages (from-to)e14052
JournalPhysiological reports
Volume7
Issue number7
DOIs
StatePublished - Apr 1 2019

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Doxorubicin
Muscles
Skeletal Muscle
Cell Count
Messenger RNA
Anthracyclines
Intraperitoneal Injections
Sprague Dawley Rats
Recurrence
Drug Therapy
Injections
Mortality
Pharmaceutical Preparations

Keywords

  • Chemotherapy
  • extensor digitorum longus
  • Ki67
  • Pax7
  • soleus

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

D'Lugos, A. C., Fry, C. S., Ormsby, J. C., Sweeney, K. R., Brightwell, C. R., Hale, T., ... Dickinson, J. M. (2019). Chronic doxorubicin administration impacts satellite cell and capillary abundance in a muscle-specific manner. Physiological reports, 7(7), e14052. https://doi.org/10.14814/phy2.14052

Chronic doxorubicin administration impacts satellite cell and capillary abundance in a muscle-specific manner. / D'Lugos, Andrew C.; Fry, Christopher S.; Ormsby, Jordan C.; Sweeney, Kaylin R.; Brightwell, Camille R.; Hale, Taben; Gonzales, Rayna J; Angadi, Siddhartha S.; Carroll, Chad C.; Dickinson, Jared M.

In: Physiological reports, Vol. 7, No. 7, 01.04.2019, p. e14052.

Research output: Contribution to journalArticle

D'Lugos, AC, Fry, CS, Ormsby, JC, Sweeney, KR, Brightwell, CR, Hale, T, Gonzales, RJ, Angadi, SS, Carroll, CC & Dickinson, JM 2019, 'Chronic doxorubicin administration impacts satellite cell and capillary abundance in a muscle-specific manner', Physiological reports, vol. 7, no. 7, pp. e14052. https://doi.org/10.14814/phy2.14052
D'Lugos, Andrew C. ; Fry, Christopher S. ; Ormsby, Jordan C. ; Sweeney, Kaylin R. ; Brightwell, Camille R. ; Hale, Taben ; Gonzales, Rayna J ; Angadi, Siddhartha S. ; Carroll, Chad C. ; Dickinson, Jared M. / Chronic doxorubicin administration impacts satellite cell and capillary abundance in a muscle-specific manner. In: Physiological reports. 2019 ; Vol. 7, No. 7. pp. e14052.
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abstract = "Anthracycline chemotherapies are effective at reducing disease recurrence and mortality in cancer patients. However, these drugs also contribute to skeletal muscle wasting and dysfunction. The purpose of this study was to assess the impact of chronic doxorubicin (DOX) administration on satellite cell and capillary densities in different skeletal muscles. We hypothesized that DOX would reduce satellite cell and capillary densities of the soleus (SOL) and extensor digitorum longus (EDL) muscles, along with muscle fiber size. Ovariectomized female Sprague-Dawley rats were randomized to receive three bi-weekly intraperitoneal injections of DOX (4 mg∙kg-1 ; cumulative dose 12 mg∙kg-1 ) or vehicle (VEH; saline). Animals were euthanized 5d following the last injection and the SOL and EDL were dissected and prepared for immunohistochemical and RT-qPCR analyses. Relative to VEH, CSA of the SOL and EDL fibers were 26{\%} and 33{\%} smaller, respectively, in DOX (P < 0.05). In the SOL, satellite cell and capillary densities were 39{\%} and 35{\%} lower, respectively, in DOX (P < 0.05), whereas in the EDL satellite cell and capillary densities were unaffected by DOX administration (P > 0.05). Proliferating satellite cells were unaffected by DOX in the SOL (P > 0.05). In the SOL, MYF5 mRNA expression was increased in DOX (P < 0.05), while in the EDL MGF mRNA expression was reduced in DOX (P < 0.05). Chronic DOX administration is associated with reduced fiber size in the SOL and EDL; however, DOX appeared to reduce satellite cell and capillary densities only in the SOL. These findings highlight that therapeutic targets to protect skeletal muscle from DOX may vary across muscles.",
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