Effects of exercise on AKT/PGC1-α/FOXO3a pathway and muscle atrophy in cisplatin-administered rat skeletal muscle

Bae, Joonsoo; Seo, Dongju; Lee, Sang Ho; Shin, Chaeyoung; Jamrasi, Parivash; Han, Jin Hee; Song, Wook

doi:10.4196/kjpp.2021.25.6.585

Cited by 10 publications

(12 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding experimental chemotherapy‐induced cachexia, loss of skeletal muscle PGC1α has been consistent across several chemotherapeutic regimens, including folfiri, folfox, sorafenib, doxorubicin and cisplatin. 6 , 8 , 28 , 29 , 38 Interestingly, in contrast to previous work, young WT male treated with cisplatin in our study did not display reductions in skeletal muscle PGC1α. We presently measured protein in quadriceps muscles, while prior work assessed PGC1α levels in gastrocnemius, soleus, and tibialis anterior muscles, which may account for discrepancy of results.…”

Section: Discussioncontrasting

confidence: 99%

“…Otherwise, mitochondrial proteins were increased in Tg compared with WT animals (Figure 5A–X ). Interestingly, despite previous evidence that cisplatin leads to reductions in PGC1α, 28 , 29 young male WT + C did not display reductions in PGC1α compared with untreated WT animals (Figure 5A ). Further, young male WT + C did not show reductions in any mitochondrial proteins assessed, including OPA1, VDAC, cytochrome‐C, and Cox IV, while Mitofusin‐2 levels were increased compared with untreated WT animals (Figure 5B–F ).…”

Section: Resultscontrasting

confidence: 64%

“…We and others have reported that cisplatin promotes significant in vivo weight loss, skeletal muscle wasting and mitochondrial alterations, including reduced PGC1α. 7 , 9 , 11 , 28 , 29 , 30 Whether this effect is worsened in aged animals or whether overexpression of skeletal muscle PGC1α is sufficient to combat cisplatin‐induced cachexia remains unknown. Thus, we treated young (2 months) and old (18 months) male and female WT and Tg mice with cisplatin for 2 weeks.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, much like muscle weakness, mitochondrial dysfunction may also precede loss of muscle mass in experimental cachexia 14,22 . Several routinely used chemotherapeutics are known to induce skeletal muscle weakness and loss of muscle mitochondrial proteins, including PGC1α 6,8,9,28,29 . In the present studies we assessed whether overexpression of skeletal muscle PGC1α could preserve muscle mass and function in mice treated with cisplatin.…”

Section: Discussionmentioning

confidence: 98%

“… 14 , 22 Several routinely used chemotherapeutics are known to induce skeletal muscle weakness and loss of muscle mitochondrial proteins, including PGC1α. 6 , 8 , 9 , 28 , 29 In the present studies we assessed whether overexpression of skeletal muscle PGC1α could preserve muscle mass and function in mice treated with cisplatin. Our findings highlight that cisplatin‐induced cachexia occurs in both male and female mice and is exacerbated in older animals compared with younger mice, with the former benefitting more from the protective effects associated with elevated muscle PGC1α.…”

Section: Discussionmentioning

confidence: 99%

See 4 more Smart Citations

PGC1α overexpression preserves muscle mass and function in cisplatin‐induced cachexia

Huot

Chatterjee

et al. 2022

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

Background Chemotherapy induces a cachectic‐like phenotype, accompanied by skeletal muscle wasting, weakness and mitochondrial dysfunction. Peroxisome proliferator‐activated receptor‐gamma coactivator‐1 alpha (PGC1α), a regulator of mitochondrial biogenesis, is often reduced in cachectic skeletal muscle. Overexpression of PGC1α has yielded mixed beneficial results in cancer cachexia, yet investigations using such approach in a chemotherapy setting are limited. Utilizing transgenic mice, we assessed whether overexpression of PGC1α could combat the skeletal muscle consequences of cisplatin. Methods Young (2 month) and old (18 month) wild‐type (WT) and PGC1α transgenic male and female mice (Tg) were injected with cisplatin (C; 2.5 mg/kg) for 2 weeks, while control animals received saline (n = 5–9/group). Animals were assessed for muscle mass and force, motor unit connectivity, and expression of mitochondrial proteins. Results Young WT + C mice displayed reduced gastrocnemius mass (male: −16%, P < 0.0001; female: −11%, P < 0.001), muscle force (−6%, P < 0.05, both sexes), and motor unit number estimation (MUNE; male: −53%, P < 0.01; female: −51%, P < 0.01). Old WT + C male and female mice exhibited gastrocnemius wasting (male: −22%, P < 0.05; female: −27%, P < 0.05), muscle weakness (male: −20%, P < 0.0001; female: −17%, P < 0.01), and loss of MUNE (male: −82%, P < 0.01; female: −62%, P < 0.05), suggesting exacerbated cachexia compared with younger animals. Overexpression of PGC1α had mild protective effects on muscle mass in young Tg + C male only (gastrocnemius: +10%, P < 0.05); however, force and MUNE were unchanged in both young Tg + C male and female, suggesting preservation of neuromuscular function. In older male, protective effects associated with PGC1α overexpression were heighted with Tg + C demonstrating preserved muscle mass (gastrocnemius: +34%, P < 0.001), muscle force (+13%, P < 0.01), and MUNE (+3‐fold, P < 0.05). Similarly, old female Tg + C did not exhibit muscle wasting or reductions in MUNE, and had preserved muscle force (+11%, P < 0.05) compared with female WT + C. Follow‐up molecular analysis demonstrated that aged WT animals were more susceptible to cisplatin‐induced loss of mitochondrial proteins, including PGC1α, OPA1, cytochrome‐C, and Cox IV. Conclusions In our study, the negative effects of cisplatin were heighted in aged animals, whereas overexpression of PGC1α was sufficient to combat the neuromuscular dysfunction caused by cisplatin, especially in older animals. Hence, our observations indicate that aged animals may be more susceptible to develop chemotherapy side toxicities and that mitochondria‐targeted strategies may serve as a tool to prevent chemotherapy‐induced muscle wasting and weakness.

show abstract