Dysregulated mitochondrial quality control and mitochondrial degeneration contribute to muscle atrophy in cancer cachexia (CC). OPA1, a key regulator of mitochondrial fusion, is downregulated in cachectic muscle whereas, BNIP3, a mitophagy regulator is upregulated and appears to contribute to mitochondrial dysfunction. We hypothesized that muscle targeted OPA1 overexpression or BNIP3 knockdown can preserve muscle mass and contractile function in an orthotopic pancreatic CC model. METHODS: Male and female C57BL/6J mice received bilateral myoAAV injections encoding OPA1 (2*10 10 viral genomes (vg)/TA), short hairpin BNIP3 (ShBNIP3; 3*10 9 vg/TA), or phosphate-buffered saline (PBS) two weeks before tumor implantation. Orthotopic tumors were induced by injecting 150,000 KPC-FC1245 cells into the pancreas of cancer groups (KPC), healthy controls received a sham injection to the pancreas. In-vivo muscle function assessments and tissue collection were performed at humane endpoint. Data were analyzed within each sex using one-way ANOVA, with alpha set at 0.05. RESULTS: In males, both OPA1 and BNIP3 demonstrated robust systemic cachexia, with reductions in muscle and fat mass (OPA1: plantaris ~-15%, p=0.0003; fat ~−47%, p< 0.0001; BNIP3: plantaris ~−20.34%, p< 0.0001; fat ~−53%, p< 0.0001) and splenomegaly (OPA1: ~+130%, p< 0.0001; BNIP3: +101%, p< 0.0001), none of which differed between KPC-sham and treatment groups, confirming treatment effects of myoAAV were localized to the TA. Despite persistent systemic cachexia, both interventions partially preserved TA muscle. OPA1 overexpression attenuated TA atrophy observed in KPC-sham (−15%, p=0.0025) with KPC-OPA1 exhibited only a non-significant (ns) ~6.3% lower TA mass compared to healthy controls, while BNIP3 knockdown similarly showed partial rescue (KPC-sham −15%, p=0.0079; KPC-ShBNIP3 −9.9%, ns). Functional impairments were also mitigated: OPA1 overexpression mitigated submaximal force deficits seen in KPC-sham (80–125 hertz (Hz); ~−26–48%, p≤0.05) while KPC-OPA1 were not significantly different from controls (~4.3–26.5% loss, ns), whereas BNIP3 knockdown markedly improved submaximal torque compared to KPC-sham (−22 to −62%, p< 0.0001) and producing higher force than controls at 20–40 Hz (+22–41%, p< 0.001), with overall greater force than KPC-sham across 10–100 Hz (p< 0.0001). Females exhibited mild systemic cachexia with limited functional impact, although treatment groups showed increased TA mass (OPA1: +9%, p=0.03; BNIP3: +4%; ns). CONCLUSION: Collectively, these findings demonstrate that OPA1 overexpression and BNIP3 knockdown provide sex-specific protection of TA muscle mass and submaximal force production in pancreatic CC. In line with our lab’s prior work of using transgenic models of Lewis Lung Carcinoma (LLC), global OPA1 overexpression enhanced TA mass and functional capacity, while global BNIP3 knockout failed to preserve muscle mass or contractile function. The present muscle-directed AAV interventions mirror these divergent outcomes, reinforcing that promoting fusion is beneficial whereas global BNIP3 suppression may be insufficient. Together, these observations indicate that localized control of mitochondrial dynamics may yield superior protection compared with global manipulation. This study was funded by the National Institute of Health (NIH) Award: R01 AR075794. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Muhyudin et al. (2026) studied this question.