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. 2023 Nov 1:14:1283674.
doi: 10.3389/fphys.2023.1283674. eCollection 2023.

Mouse skeletal muscle adaptations to different durations of treadmill exercise after the cessation of FOLFOX chemotherapy

Jessica L Halle  1 , Brittany R Counts  1 , Quan Zhang  1 , Kylie M James  1 , Melissa J Puppa  2 , Stephen E Alway  3 , James A Carson  1
Affiliations

Mouse skeletal muscle adaptations to different durations of treadmill exercise after the cessation of FOLFOX chemotherapy

Jessica L Halle et al. Front Physiol. .

Abstract

FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy is a treatment for colorectal cancer that can induce persistent fatigue and metabolic dysfunction. Regular exercise after chemotherapy cessation is widely recommended for cancer patients and has been shown to improve fatigue resistance in mice. However, gaps remain in understanding whether the early systemic and skeletal muscle adaptations to regular exercise are altered by prior FOLFOX chemotherapy treatment. Furthermore, the effects of exercise duration on early metabolic and skeletal muscle transcriptional adaptations are not fully established. Purpose: Investigate the effects of prior FOLFOX chemotherapy treatment on the early adaptations to repeated short- or long-duration treadmill exercise, including the fasting regulation of circulating metabolic regulators, skeletal muscle COXIV activity and myokine/exerkine gene expression in male mice. Methods: Male C57BL6/J mice completed 4 cycles of FOLFOX or PBS and were allowed to recover for 4-weeks. Subsets of mice performed 14 sessions (6 d/wk, 18 m/min, 5% grade) of short- (10 min/d) or long-duration (55 min/d) treadmill exercise. Blood plasma and muscle tissues were collected 48-72 h after the last exercise bout for biochemical analyses. Results: Long-duration exercise increased fasting plasma osteocalcin, LIF, and IL-6 in healthy PBS mice, and these changes were ablated by prior FOLFOX treatment. Slow-oxidative soleus muscle COXIV activity increased in response to long-duration exercise in PBS mice, which was blocked by prior FOLFOX treatment. Fast-glycolytic plantaris muscle COXIV activity increased with short-duration exercise independent of FOLFOX administration. There was a main effect for long-duration exercise to increase fasting muscle IL-6 and COXIV mRNA expression independent of FOLFOX. FOLFOX administration reduced muscle IL-6, LIF, and BDNF mRNA expression irrespective of long-duration exercise. Interestingly, short-duration exercise suppressed the FOLXOX induction of muscle myostatin mRNA expression. Conclusion: FOLFOX attenuated early exercise adaptations related to fasting circulating osteocalcin, LIF, and IL-6. However, prior FOLFOX treatment did not alter the exercise adaptations of plantaris muscle COXIV activity and plasma adiponectin. An improved understanding of mechanisms underlying exercise adaptations after chemotherapy will provide the basis for successfully treating fatigue and metabolic dysfunction in cancer survivors.

Keywords: COXIV; IL-6; LIF; cancer survivors; exerkines; myokines; myostatin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
Skeletal muscle and systemic adaptations to 14 sessions of repeated of short- or long-duration treadmill exercise in healthy mice. (A) Study Design: Male C57BL/6J mice performed 14 sessions (6 d/wk, 18 m/min, 5% grade) of 0 min/d (sedentary), 10 min/d (short-duration), or 55 min/d (long-duration) treadmill exercise. Blood plasma and muscle tissues were collected 48–72 hrs after the last exercise bout, after a 12-hr fast. (B) COXIV enzyme activity in oxidative soleus muscle and (C) glycolytic plantaris muscle in healthy PBS mice, 0 min/d: N = 13, 10 min/d: N = 9, and 55 min/d: N = 5 for soleus and N = 10 for plantaris. Fasting plasma concentrations of (D) adiponectin, (E) uncarboxylated osteocalcin (Glu-OCN), (F) leukemia inhibitory factor (LIF), and (G) interleukin-6 (IL-6) in healthy PBS mice, 0 min/d: N = 10–13, 10 min/d: N = 8–9 and 55 min/d: N = 10. (H) Representative Western blot and quantified phosphorylated (p-) to total STAT3 (Y705) protein expression with Coomassie Blue stain as a protein loading control in healthy PBS mice, 0 min/d: N = 12–13, 10 min/d: N = 9, and 55 min/d: N = 10. Data is presented as mean ± SEM. Data is analyzed using One-Way ANOVA with Tukey’s posthoc. Statistical significance was set to p < 0.05. * different from 0 min/d; ^ different from 10 min/d.
FIGURE 2
FIGURE 2
Effect of prior FOLFOX chemotherapy treatment on muscle and systemic adaptations to 14 sessions of repeated short- or long-duration treadmill exercise. (A) Study Design: Male C57BL/6J mice were injected with 4 cycles (1 cycle = 1 injection every other wk) of FOLFOX (5-Fluorouracil 30 mg/kg, Oxaliplatin 6 mg/kg, Leucovorin 90 mg/kg) and were allowed to recover for 2-weeks after the last injection. Subsets of mice performed 14 sessions of (6 d/wk, 18 m/min, 5% grade) of 0 min/d (sedentary), 10 min/d (short-duration), or 55 min/d (long-duration) treadmill exercise. Blood plasma and muscle tissues were collected 48–72 hrs after the last exercise bout, after a 12-hr fast. (B) Soleus muscle and (C) plantaris muscle COXIV enzyme activity in sedentary and exercise trained mice recovering from FOLFOX chemotherapy; 0 min/d (N = 9–12), 10 min/d (N = 9–10) and 55 min/d (N = 10). Fasting plasma concentrations of (D) adiponectin, (E) uncarboxylated osteocalcin (Glu-OCN), (F) leukemia inhibitory factor (LIF), and (G) interleukin-6 (IL-6) in FOLFOX mice; 0 min/d: N = 9–12, 10 min/d: N = 9–10, and 55 min/d: N = 10. (H) Representative Western blot and quantified phosphorylated (p-) to total STAT3 (Y705) protein expression with Coomassie Blue stain as a protein loading control in mice recovering from FOLFOX; 0 min/d: N = 12, 10 min/d: N = 10, and 55 min/d: N = 10. Data is presented as mean ± SEM. Data is analyzed using One-Way ANOVA with Tukey’s posthoc. Statistical significance was set to p < 0.05. * different from 0 min/d; ^ different from 10 min/d.
FIGURE 3
FIGURE 3
Effects of prior FOLFOX chemotherapy treatment on skeletal muscle myokine/exerkine gene expression following repeated long-duration exercise bouts. Red gastrocnemius expression of (A) IL-6, (B) LIF, (C) myostatin, (D) brain-derived neurotrophic factor (BDNF), (E) IL-15, and (F) irisin mRNA in PBS and FOLFOX sedentary and long-duration exercise trained mice. GAPDH was used as the housekeeping gene. 0 min/d: PBS N = 13, FOLFOX N = 12, 55 min/d: PBS N = 10, FOLFOX N = 10. Data is presented as mean ± SEM. Data is analyzed using Two-Way ANOVA. Statistical significance was set to p < 0.05. Bold and italicized values are significant. # main effect of FOLFOX, $ main effect of 55 min/d (long-duration) exercise.
FIGURE 4
FIGURE 4
Effect of prior FOLFOX chemotherapy treatment on skeletal muscle metabolic-related gene expression following repeated bouts of long-duration treadmill exercise. Red gastrocnemius expression of (A) COXIV, (B) insulin-like growth factor 1 (IGF-1), (C) glucose transporter type 4 (GLUT4), (D) CD36, (E) carnitine palmitoyltransferase 1B (CPT1B), (F) AdipoR1, (G) G protein-coupled receptor class C group 6 member A (GPRC6A), and (H) glycoprotein 130 (gp130) mRNA in PBS and FOLFOX sedentary (0 min/d) and long-duration (55 min/d) exercise trained mice. GAPDH was used as the housekeeping gene. (0 min/d): PBS N = 12–13, FOLFOX N = 12, (55 min/d): PBS N = 10, FOLFOX N = 10. Data is presented as mean ± SEM. Data is analyzed using Two-Way ANOVA and Tukey’s post hoc. Statistical significance was set to was set to p < 0.05. Bold and italicized values are significant. * with bracket denotes significant difference between respective groups. # main effect of FOLFOX, $ main effect of (55 min/d) (long-duration) exercise.
FIGURE 5
FIGURE 5
The effect of repeated short-duration treadmill exercise sessions on skeletal muscle COXIV and myokine/exerkine gene expression in FOLFOX treated mice. Red gastrocnemius expression of (A) COXIV, (B) LIF, (C) IL-6, (D) myostatin, (E) BDNF, and (F) IL-15 mRNA expression in PBS and FOLFOX sedentary (0 min/d) and short-duration (10 min/d) exercise trained mice. GAPDH was used as the housekeeping gene. (0 min/d): PBS N = 13, FOLFOX N = 12, (10 min/d): PBS N = 9, FOLFOX N = 10. Data is presented as mean ± SEM. Data is analyzed using Two-Way ANOVA and Tukey’s post hoc. Statistical significance was set to was set to p < 0.05. Bold and italicized values are significant. * with bracket denotes significant difference between respective groups. # main effect of FOLFOX, $ main effect of (10 min/d) (short-duration) exercise.
FIGURE 6
FIGURE 6
Association between skeletal muscle LIF mRNA expression and muscle COXIV activity and in sedentary and exercised PBS or FOLFOX treated mice. (A) Pearson r correlation of red gastrocnemius LIF mRNA expression with plantaris muscle COXIV enzyme activity and (B) soleus muscle COXIV enzyme activity in PBS mice. (C) Pearson r correlation of red gastrocnemius LIF mRNA expression with plantaris muscle COXIV enzyme activity and (B) soleus muscle COXIV enzyme activity in FOLFOX treated mice. Statistical significance is set to p < 0.05. Bold and italicized p-values denotes significance. Circles represent PBS treated mice, Triangles represent FOLFOX treated mice. White: 0 min/d, Grey: 10 min/d, and Black: 55 min/d.
FIGURE 7
FIGURE 7
Association between plasma LIF and muscle myokine/exerkine mRNA expression in sedentary and exercised PBS or FOLFOX treated mice. (A) Pearson r correlation of fasting plasma LIF with red gastrocnemius muscle IL-6 mRNA expression and (B) myostatin mRNA expression in PBS mice. (C) Pearson r correlation of fasting plasma LIF with red gastrocnemius muscle IL-6 mRNA expression and (D) myostatin mRNA expression in FOLFOX treated mice. Statistical significance is set to p < 0.05. Bold and italicized p-values denotes significance.
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