Estrogens and Antioxidants Prevent the Formation of Tubular Aggregates in Aging Male Mice.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Antioxidants*/pharmacology ; Aging*/metabolism ; Aging*/drug effects ; Estrogens*/pharmacology ; Sarcoplasmic Reticulum*/metabolism ; Sarcoplasmic Reticulum*/drug effects; Calcium/metabolism ; Oxidative Stress/drug effects ; Stromal Interaction Molecule 1/metabolism ; Stromal Interaction Molecule 1/genetics ; ORAI1 Protein/metabolism ; ORAI1 Protein/genetics ; Animals ; Male ; Mice

Tubular aggregates (TAs), ordered arrays of sarcoplasmic reticulum (SR) tubes, are the main morphological alteration found in muscle biopsies from patients affected by TA myopathy (TAM). TAM has been linked to mutations in the genes encoding for STIM1 and ORAI1, which are two proteins that mediate Store-Operated Ca²⁺ entry (SOCE). SOCE is a mechanism that allows recovery of extracellular Ca²⁺ during fatigue, when the SR becomes depleted. As TAs also form in fast-twitch muscle fibers of aging male mice (not in females), we studied the effect of sex hormones on the aggregation of TAs during aging. We administered estrogen (ad libitum in drinking water) to male mice from 10 to 18 months of age and then evaluated the following: (a) the presence of TAs using histology and electron microscopy (EM); (b) oxidative stress, a mechanism that could underlie damage to proteins and membranes (and possibly their accumulation in TAs); and (c) SOCE function during ex vivo stimulation in the presence or absence of external Ca²⁺ or SOCE blocker (BTP-2). The results collected indicate that treatment with estrogen (a) significantly reduced the formation of TAs; (b) reduced oxidative stress, which was elevated in aging male mice; and (c) restored SOCE, i.e., the capability of aged EDL muscles to use external Ca²⁺ by promoting maintenance of Ca²⁺ Entry Units (CEUs, the intracellular junctions that mediate SOCE). Finally, we also show that formation of TAs is reduced by treatment of mice with N-acetilcysteine (NAC), a potent antioxidant also administered ad libitum in drinking water.

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R01 AR059646 United States AR NIAMS NIH HHS; subcontract of AR059646 National Institutes of Health USA to FP; GGP19231 Italian Telethon ONLUS to FP and VS; B63C22000610006 Center for Gene Therapy and Drugs Based on RNA Technology, funded in the framework of the National Recovery and Resilience Plan (NRRP), M4C2 Inv, 1.4 - Spoke 1 to VS

Keywords: electron microscopy; sarcoplasmic reticulum; skeletal muscle; store-operated calcium entry

0 (Antioxidants)
0 (Estrogens)
SY7Q814VUP (Calcium)
0 (Stromal Interaction Molecule 1)
0 (ORAI1 Protein)

Date Created: 20250927 Date Completed: 20250927 Latest Revision: 20251001

20260130

PMC12470441

10.3390/ijms26189122

41009681