1. Academic Validation
  2. Sirolimus treatment induces dose-dependent involution of the thymus with elevated cellular respiration in BALB/c mice

Sirolimus treatment induces dose-dependent involution of the thymus with elevated cellular respiration in BALB/c mice

  • Am J Transl Res. 2022 Jul 15;14(7):4678-4687.
Saeeda Almarzooqi 1 Charu Sharma 2 Dhanya Saraswathiamma 1 Ahmed R Alsuwaidi 3 Noura Hadid 3 Abdul-Kader Souid 3 Alia Albawardi 1
Affiliations

Affiliations

  • 1 Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University United Arab Emirates.
  • 2 Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University United Arab Emirates.
  • 3 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University United Arab Emirates.
PMID: 35958488
Abstract

Several in vitro and in vivo studies have shown that the mammalian target of rapamycin (mTOR) inhibitor sirolimus (rapamycin) suppresses thymus cellular respiration. The objective of this study is to investigate the chronic dose-dependent effects of sirolimus in the thymus. This was monitored using body weight, histomorphology, Caspase-3 expression, cytochrome C immunohistochemistry, and cellular bioenergetics as surrogate biomarkers. BALB/c mice received intraperitoneal injections of either sirolimus (2.5, 5, or 10 µg/g) or dimethyl sulfoxide (0.1 µL/g) as a control for 4 weeks. At the end of the treatment, fragments were collected from the thymus, small intestine, adrenal gland, and kidney. They were processed for assessing histologic changes, measuring cellular respiration and ATP levels. Immunohistochemical stain of Caspase-3 and cytochrome C was performed on paraffin-embedded tissue. The treated Animals exhibited a dose-dependent reduction in weight gain despite adequate food intake. Sirolimus produced significant thymic derangements, manifested by dose-dependent tissue involution, increased cortical apoptotic bodies, increased caspase-3-positive lymphocytes, and increased rate of cellular respiration without a concomitant increase in cellular ATP. There were no similar changes in cellular ATP in the other assessed organs. The effects on thymic cellular bioenergetics suggest mitochondrial derangements, uncoupling of Oxidative Phosphorylation, and induction of Apoptosis.

Keywords

Thymus; cellular bioenergetics; cellular respiration; sirolimus.

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