Hindlimb unloading induces time-dependent disruption of testicular histology in mice.

Mechanical unloading of the body in the hindlimb unloaded (HU) mice induces pathology in multiple organs, but the effects on testes are poorly characterized. We investigated the histology and Raman spectroscopy of the mouse testes following HU condition. We divided male, c57BL/6j mice into ground-based controls or experimental groups for two and four weeks of HU. The testes tissues were dissected after euthanasia to investigate histological and Raman spectroscopic analysis. We found an HU-induced atrophy of testes irrespective of the time duration (p < 0.05). Histological analysis revealed that the HU induced epithelial thinning, luminal widening, and spermatozoa decline in the seminiferous tubules of the mouse testes. In addition, we found a thickening of the epididymal epithelia and tunica albuginea. These changes were accompanied by a generalized depression in the Raman spectra, indicating an altered concentration and/or orientation of several molecules. We also report reduced signal intensities of hydroxyproline and tryptophan, potentially contributing to testicular pathology during HU. Taken together, our findings indicate that the two or four weeks of HU induce disruption of testicular architecture and molecular phenotypes. Our results may have implications for understanding and/or treating male infertility associated with prolonged bed rest and spaceflight.

Suppression of endoplasmic reticulum stress prevents disuse muscle atrophy in a mouse model of microgravity.

BACKGROUND: Hind-limb unloaded (HLU) mouse model exhibits skeletal muscle atrophy and weakness mimicking the conditions such as prolonged spaceflight. However, the molecular mechanisms and interventions of muscle loss during muscle unloading remain elusive. Dysfunction of protein folding by ednoplasmic reticulum (ER), a condition called ER stress, is implicated in diseases of various cell types, but its contribution to skeletal muscle detriment remains elusive. In this study, we investigated the contribution of ER stress to muscle atrophy. METHODS: Sixteen-week-old c57BL/6j male mice were grouped into ground-based controls and HLU group, which was subsequently injected with injected saline (HLU-sal.) or pan-ER stress inhibitor 4-PBA (100mg/kg/d; HLU- 4PBA) via intraperitoneal injections for three weeks. RESULTS: Three weeks of HLU resulted in reduction in muscle mass and strength, which were restored with 4PBA injections. We also report myofibers atrophy, myonuclear apoptosis, and aterations in the expressions of genes associated with ER stress, apoptosis, and calcium dysregulation. These findings were reversed by 4-PBA treatment. CONCLUSION: Altogether, our results indicate that ER stress contributes to muscle atrophy in HLU conditions. We suggest that blocking ER stress may be an effective pharmacological therapy to prevent muscle weakness and atrophy during prolonged muscle unloading.

Mitigating sarcoplasmic reticulum stress limits disuse-induced muscle loss in hindlimb unloaded mice.

Muscle disuse in the hindlimb unloaded (HU) mice causes significant atrophy and weakness. However, the cellular and molecular mechanisms driving disuse-muscle atrophy remain elusive. We investigated the potential contribution of proteins dysregulation by sarcoplasmic reticulum (SR), a condition called SR stress, to muscle loss during HU. Male, c57BL/6j mice were assigned to ground-based controls or HU groups treated with vehicle or 4-phenylbutyrate (4-PBA), a potent inhibitor of SR stress, once a day for three weeks. We report that the 4-PBA reduced the SR stress and partly reversed the muscle atrophy and weakness in the HU mice. Transcriptome analysis revealed that several genes were switched on (n = 3688) or differentially expressed (n = 1184) due to HU. GO, and KEGG term analysis revealed alterations in pathways associated with the assembly of cilia and microtubules, extracellular matrix proteins regulation, calcium homeostasis, and immune modulation during HU. The muscle restoration with 4-PBA partly reversed these changes along with differential and unique expression of several genes. The analysis of genes among the two comparisons (HU-v vs. control and HU-t vs. HU-v.) shows 841 genes were overlapped between the two comparisons and they may be regulated by 4-PBA. Altogether, our findings suggest that the pharmacological suppression of SR stress may be an effective strategy to prevent disuse-induced muscle weakness and atrophy.