Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jan 6;26(1):414.
doi: 10.3390/ijms26010414.

Role of PI3 Kinases in Cell Signaling and Soleus Muscle Atrophy During Three Days of Unloading

Ksenia A Zaripova  1 , Svetlana P Belova  1 , Tatiana Y Kostrominova  2 , Boris S Shenkman  1 , Tatiana L Nemirovskaya  1
Affiliations

Role of PI3 Kinases in Cell Signaling and Soleus Muscle Atrophy During Three Days of Unloading

Ksenia A Zaripova et al. Int J Mol Sci. .

Abstract

During skeletal muscle unloading, phosphoinositide 3-kinase (PI3K), and especially PI3K gamma (PI3Kγ), can be activated by changes in membrane potential. Activated IP3 can increase the ability of Ca2+ to enter the nucleus through IP3 receptors. This may contribute to the activation of transcription factors that initiate muscle atrophy processes. LY294002 inhibitor was used to study the role of PI3K in the ATP-dependent regulation of skeletal muscle signaling during three days of unloading. Inhibition of PI3K during soleus muscle unloading slows down the atrophic processes and prevents the accumulation of ATP and the expression of the E3 ubiquitin ligase MuRF1 and ubiquitin. It also prevents the increase in the expression of IP3 receptors and regulates the activity of Ca2+-dependent signaling pathways by reducing the mRNA expression of the Ca2+-dependent marker calcineurin (CaN) and decreasing the phosphorylation of CaMKII. It also affects the regulation of markers of anabolic signaling in unloaded muscles: IRS1 and 4E-BP. PI3K is an important mediator of skeletal muscle atrophy during unloading. Developing strategies for the localized skeletal muscle release of PI3K inhibitors might be one of the future treatments for inactivity and disease-induced muscle atrophy.

Keywords: ATP; MuRF1; PI3 kinase; muscle atrophy; unloading.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic summarizing the signaling resulting in PI3 kinase activation.
Figure 2
Figure 2
Evaluation of soleus muscle mass in control (3C), three-day unloaded (3HS), and LY294002-treated three-day unloaded (3LY) rats. N = 8. * indicates a significant difference from the control, and # indicates a significant difference from the 3HS group, p < 0.05.
Figure 3
Figure 3
Evaluation of phospho-PI3Kγ (A) and IP3 (B) contents in the muscles of control (3C), three-day unloaded (3HS), and LY294002-treated three-day unloaded (3LY) rats. The level of phosphorylated PI3K (p-PI3K) was normalized to the level of GAPDH in each sample (A). N = 8. * indicates a significant difference from the control, and # indicates a significant difference from the 3HS group, p < 0.05.
Figure 4
Figure 4
Evaluation of ATP (A) and p-AMPK (B) contents in the muscles of control (3C), three-day unloaded (3HS), and LY294002-treated three-day unloaded (3LY) rats. Phosphorylated AMPK (p-AMPK) was normalized to the total AMPK content in each sample (B). N = 8. * indicates a significant difference, p < 0.05.
Figure 5
Figure 5
Evaluation of phospho-CaMKII content (A) and CaN mRNA expression (B) in the muscles of control (3C), three-day unloaded (3HS), and LY294002-treated three-day unloaded (3LY) rats. Phosphorylated CaMKII was normalized to the total CaMKII content in each sample (A). N = 8. * indicates a significant difference, p < 0.05.
Figure 6
Figure 6
Evaluation of IP3R content in the muscles of control (3C), three-day unloaded (3HS), and LY294002-treated three-day unloaded (3LY) rats. The content of IP3R was normalized to the GAPDH content in each sample. N = 8. * indicates a significant difference, p < 0.005.
Figure 7
Figure 7
Evaluation of MuRF1 (A), MAFbx (B), ubiquitin (C), and TFEB (D) mRNA expression and phospho-FOXO3 (E) content in the muscles of control (3C), three-day unloaded (3HS), and LY294002-treated three-day unloaded (3LY) rats. Phosphorylated FOXO3 content was normalized to the total FOXO3 content in each sample (E). N = 8. * indicates a significant difference from the control, and # indicates a significant difference from the 3HS group, p < 0.05.
Figure 8
Figure 8
Evaluation of IRS1 (A), phospho-4EBP1 (B), phospho-Akt (C), and total/phospho-S6 (D) contents in the muscles of control (3C), three-day unloaded (3HS), and LY294002-treated three-day unloaded (3LY) rats. IRS1 content was normalized to the content of GAPDH in each sample (A). Phosphorylated 4EBP1, Akt, and S6 contents were normalized to the total 4EBP1, Akt, and S6 contents in each sample (B). N = 8. * indicates a significant difference, p < 0.05.
See this image and copyright information in PMC

References

    1. Mirzoev T.M., Shenkman B.S. Regulation of Protein Synthesis in Inactivated Skeletal Muscle: Signal Inputs, Protein Kinase Cascades, and Ribosome Biogenesis. Biochemistry. 2018;83:1299–1317. doi: 10.1134/S0006297918110020. - DOI - PubMed
    1. Ingalls C.P., Warren G.L., Armstrong R.B. Intracellular Ca2+ transients in mouse soleus muscle after hindlimb unloading and reloading. J. Appl. Physiol. 1999;87:386–390. doi: 10.1152/jappl.1999.87.1.386. - DOI - PubMed
    1. Zaripova K.A., Kalashnikova E.P., Belova S.P., Kostrominova T.Y., Shenkman B.S., Nemirovskaya T.L. Role of Pannexin 1 ATP-Permeable Channels in the Regulation of Signaling Pathways during Skeletal Muscle Unloading. Int. J. Mol. Sci. 2021;22:10444. doi: 10.3390/ijms221910444. - DOI - PMC - PubMed
    1. Shenkman B.S., Nemirovskaya T.L. Calcium-dependent signaling mechanisms and soleus fiber remodeling under gravitational unloading. J. Muscle Res. Cell Motil. 2008;29:221–230. doi: 10.1007/s10974-008-9164-7. - DOI - PubMed
    1. Kravtsova V.V., Matchkov V.V., Bouzinova E.V., Vasiliev A.N., Razgovorova I.A., Heiny J.A., Krivoi I.I. Isoform-specific Na,K-ATPase alterations precede disuse-induced atrophy of rat soleus muscle. BioMed Res. Int. 2015;2015:720172. doi: 10.1155/2015/720172. - DOI - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources