Marker Of Mitochondrial Quality Control In Mice Gastrocnemius Muscle Following Recovery From Cisplatin Chemotherapy Treatment.

BACKGROUND: Cisplatin is a common chemotherapy drug however, its use is associated with notably muscle wasting. Evidence suggests cisplatin-induced atrophy is caused by mitochondrial dysfunction stemming from changes to biogenesis, mitophagy, and fusion and fission, termed mitochondrial quality control. There is a lack of evidence on the long-term effect of cisplatin on mitochondrial; thus, the aim was to investigate the long-term effects of cisplatin on markers of mitochondrial quality control. METHODS: CD2F1 mice, aged 5-6 months, were divided into two groups: Cisplatin (Cis) or Vehicle (Veh), n = 10/group. Cis group received a chemotherapy cycle of once weekly injection of 5 mg/kg body weight of Cis for four weeks. Veh mice received saline. Muscle was collected 28 days after the last chemotherapy dose. mRNA content of mitochondrial fusion and fission (Mfn1, Mfn2, DRP1, and FIS1), biogenesis (mtDNA, Tfam and PGC-1α), and mitophagy (Opa1, Gabarapl, Park2, Beclin, and P62) were analyzed in the gastrocnemius muscle. Data were analyzed using an independent t-test and presented as mean ± standard error. RESULTS: Cis treated mice had significantly lower body weight after recover (Veh = 33.04 ± 0.36 vs Cis = 29.87 ± 0.45 g, p < 0.0001) and significantly lower gastrocnemius mass (Veh = 147.5 ± 2.15 vs 139.20 ± 1.50 mg; p = 0.008). Our analysis showed that PGC-1α, a marker for mitochondrial biogenesis, was significantly downregulated in gastrocnemius muscle of mice treated with Cisplatin (p < 0.005) and p62 a cell-autophagy marker exhibited a tendency towards downregulation (p = 0.06). All other markers were non-significant. CONCLUSIONS: Our data does not suggest a sustained downregulation of commonly measured genes related to mitochondrial quality control following 28 days of recovery of a cisplatin chemotherapy cycle. The significant difference in PGC-1α and trend in p62 mRNA suggests further investigation of protein expression in these pathways and suggests future studies examining other mechanisms that influence muscle mass recovery.