IP3 Receptors Mediate Calcium and Anabolic Signaling Associated with Muscle Atrophy upon 3-Day Hind Limb Unloading in Rats

---

Ksenia A. Zaripova^1,a, Roman O. Bokov^1,b, Kristina A. Sharlo^1,c*, Svetlana P. Belova^1,d*, and Tatiana L. Nemirovskaya^1,e*

¹Institute of Biomedical Problems, Russian Academy of Sciences, 123007 Moscow, Russia

^* To whom correspondence should be addressed.

Received: March 10, 2025; Revised: August 7, 2025; Accepted: August 22, 2025

---

Skeletal muscle unloading results in muscle atrophy associated with the upregulation of proteolytic genes and suppression of protein synthesis, often accompanied by altered calcium signaling. Here, we used the inositol trisphosphate receptor (IP3R) inhibitor aminoethoxydiphenyl borate (2-APB) to explore the hypothesis that these changes are mediated by IP3Rs. Male Wistar rats were divided into 4 groups: (i) control, (ii) control with daily injections of 2-APB, (iii) 3 days of hind limb suspension, (iv) 3 days of hind limb suspension with daily administration of 2-APB. At the end-point, soleus muscles from the animals were analyzed by Western blotting for the markers of calcium, anabolic, and catabolic signaling. The 3-day hind limb unloading resulted in a decreased muscle weight index, upregulation of the anabolic suppressor pThr56-eEF2, downregulation of anabolic signaling via the mTOR pathway and rRNA expression, as well as the increase in the content of nuclear pThr286-CaMKII (p < 0.05) and cytosolic calcineurin A. While 2-APB did not affect the mTOR-governed changes in anabolism and catabolism, it significantly attenuated alterations in the calcium-dependent targets, such as CaMKII, calcineurin, and eEF2. By contrast, proteolytic signaling (expression of MuRF1, atrogin-1, Ulk1, and ubiquitin mRNAs) after 3-day hind limb unloading was equally upregulated in the control and 2-APB-treated animals. These results suggest that IP3Rs are involved in the unloading-induced muscle atrophy by controlling the nuclear content of calcium; however, they are dispensable for reduced mTOR activity and altered metabolism.

---

KEY WORDS: IP3 receptors, atrophy, m soleus, rRNA, unloading

DOI: 10.1134/S0006297925602497

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

---