Promoting mitochondrial fusion is protective against cancer-induced muscle detriments in males and females

Authors

• Francielly F. Morena, University of Arkansas, Fayetteville
• Seongkyun Lim, University of Arkansas, Fayetteville
• Ana Regina Cabrera, University of Arkansas, Fayetteville
• Toby L. Chambers, University of Arkansas, Fayetteville
• Pieter J. Koopmans, University of Arkansas, Fayetteville
• Stavroula Tsitanou, University of Arkansas, Fayetteville
• Sabin Khadgi, University of Arkansas, Fayetteville
• Calvin Peterson, University of Arkansas, Fayetteville
• Eleanor R. Schrems, University of Arkansas, Fayetteville
• Ruqaiza Muhyudin, University of Arkansas, Fayetteville
• Sepideh Shakeri, University of Arkansas, Fayetteville
• Kevin Zhao, University of Arkansas, Fayetteville
• Devan Mishra, University of Arkansas, Fayetteville
• Tyrone A. Washington, University of Arkansas, Fayetteville
• Kevin A. Murach, University of Arkansas, Fayetteville
• Nicholas P. Greene, University of ArkansasFollow

Document Type

Article

Publication Date

8-11-2025

Keywords

Lewis Lung Carcinoma, BGP-15, OPA1, Mitochondrial dynamics, Muscle contractility

Abstract

Background Skeletal muscle atrophy during cancer-induced cachexia remains a significant challenge in cancer management. Mitochondrial defects precede muscle mass and functional losses in models of cancer cachexia (CC). We hypothesized targeting Opa1-a key regulator of mitochondrial fusion-can attenuate LLC-induced CC outcomes.

Methods We utilized 1) in vivo transgenic Opa1 overexpression (OPA1 TG) in LLC-induced CC in vivo, and 2) BPG15 administration to induce Opa1 in vitro and in vivo.

Results OPA1 TG attenuated plantaris, gastrocnemius, and EDL loss with LLC in males and alleviated gastrocnemius loss infemales. OPA1 TG had greater mitochondrial respiration in plantaris and white gastrocnemius, and lowered pMitoTimer Red Puncta (-63%), a proxy for mitophagy in males. OPA1 TG protected muscle contractility at physiological stimulation frequencies by up to 60% in female LLC mice. OPA1 TG enhanced the ratio of OPA1/DRP1 protein content-a proxy for fusion and fission balance-in males andfemales. In vitro, BGP-15 attenuated LLC conditioned media-induced myotube atrophy by similar to 9% concomitant with suppression of the transcriptional factor FoxO3, autophagy markers, and inflammatory cytokines. In vivo, BGP-15 improved contractility at lower frequencies (10-60 Hz), with LLC-BGP-15 showing up to 20% greater torque than LLC-control. BGP-15 treated LLC animals had 71% fewer pMitoTimer red puncta, suggesting attenuated mitophagy.

Conclusions Promoting mitochondrial fusion via OPA1 induction improved cachectic outcomes in mice. Targeting OPA1providing provides a promising therapeutic approach for CC treatment.

Comments

Web of Science

Springer

Citation

Morena, F., Lim, S., Cabrera, A.R. et al. Promoting mitochondrial fusion is protective against cancer-induced muscle detriments in males and females. BMC Cancer 25, 1300 (2025). https://doi.org/10.1186/s12885-025-14630-x

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