Background: Breast cancer patients are commonly treated with sequential administrations of epirubicin–cyclophosphamide (EC) and paclitaxel (TAX). The chronic effect of this treatment induces skeletal muscle alterations, but the specific effect of each chemotherapy agent is unknown. This study aimed to investigate the effect of EC or TAX administration on skeletal muscle homeostasis in breast cancer patients.Methods: Twenty early breast cancer patients undergoing EC followed by TAX chemotherapies were included. Two groups of 10 women were established and performed vastus lateralis skeletal muscle biopsies either before the first administration (pre) of EC (50 ± 14 years) or TAX (50 ± 16 years) and 4 days later (post). Mitochondrial respiratory capacity recording, reactive oxygen species production, western blotting and histological analyses were performed.Results: Decrease in muscle fibres cross‐sectional area was only observed post‐EC (−25%; P < 0.001), associated with a reduction in mitochondrial respiratory capacity for the complex I (CI)‐linked substrate state (−32%; P = 0.001), oxidative phosphorylation (OXPHOS) by CI (−35%; P = 0.002), CI&CII (−26%; P = 0.022) and CII (−24%; P = 0.027). If H₂O₂ production was unchanged post‐EC, an increase was observed post‐TAX for OXPHOS by CII (+25%; P = 0.022). We found a decrease in makers of mitochondrial content, as shown post‐EC by a decrease in the protein levels of citrate synthase (−53%; P < 0.001) and VDAC (−39%; P < 0.001). Despite no changes in markers of mitochondrial fission, a decrease in the expression of a marker of mitochondrial inner‐membrane fusion was found post‐EC (OPA1; −60%; P < 0.001). We explored markers of mitophagy and found reductions post‐EC in the protein levels of PINK1 (−63%; P < 0.001) and Parkin (−56%; P = 0.005), without changes post‐TAX. An increasing trend in Bax protein level was found post‐EC (+96%; P = 0.068) and post‐TAX (+77%; P = 0.073), while the Bcl‐2 level was decreased only post‐EC (−52%; P = 0.007). If an increasing trend in TUNEL‐positive signal was observed post‐EC (+68%; P = 0.082), upregulation was highlighted post‐TAX (+86%; P < 0.001), suggesting activation of the apoptosis process.Conclusions: We demonstrated that a single administration of EC induced, in only 4 days, skeletal muscle atrophy and mitochondrial alterations in breast cancer patients. These alterations were characterized by reductions in mitochondrial function and content as well as impairment of mitochondrial dynamics and an increase in apoptosis. TAX administration did not worsen these alterations as this group had already received EC during the preceding weeks. However, it resulted in an increased apoptosis, likely in response to the increased H₂O₂ production.

Ischemia-reperfusion injury leads to severe muscular damage. Even if prompt revascularization is the treatment of choice, muscular alterations can lead to severe sequalae as mitochondrial dysfunction. Accordingly, adjunctive strategies are needed to overcome the muscular damage. Mitochondrial transplantation has shown beneficial effects in cardiac ischemia-reperfusion, but its role in peripheral muscle is not well established. In this study, we found that mitochondrial transplantation partially restored muscular function when submitted to ischemia reperfusion.

Cancer‐related fatigue (CRF) is a multifactorial symptom commonly experienced by breast cancer patients treated with chemotherapy (CT) that impairs quality of life and may influence cancer recurrence by reducing treatment compliance. This cohort study examined the kinetics of CRF throughout CT in breast cancer patients and determined its relationship with exercise‐related variables. One hundred breast cancer patients were included. Three time points were investigated: pre‐CT, 8 weeks, and post‐CT. Patients were categorized as fatigued or non‐fatigued according to their FACIT‐F score. Exercise capacity (assessed using the 6‐minute walking test), muscle mass and force, neuromuscular fatigue, and physical activity level were measured. Among the seven patterns of CRF trajectories identified, three represented 78% of the fatigued patients. Fatigued patients exhibited reduced exercise capacity compared to non‐fatigued patients during CT (p = 0.001). This was associated with greater knee extensor (p < 0.001) and handgrip (p = 0.009) neuromuscular fatigue and lower physical activity level (p < 0.001) in fatigued patients. The model combining knee extensors neuromuscular fatigue (p = 0.007) and force (p = 0.081), 6‐minute walking test distance (p < 0.001) and physical activity level (p = 0.029) explained 39% of the variance in the FACIT‐F score evolution from pre‐ to post‐CT. The dissociation between fatigued versus non‐fatigued patients highlighted that CRF was associated with altered exercise capacity and neuromuscular fatigue. Exercise‐related variables seem to play an important role in CRF evolution during CT, suggesting that exercise training should be initiated at the start of CT.

Weight cycling is a major challenge in obesity management. Caloric restriction is known to promote this phenomenon, but the impact of macronutrient changes during dieting remains unclear. This study aimed to determine the role of macronutrient changes in weight maintenance without caloric restriction by alternating between two hypercaloric diets: a high-carbohydrate, high-fat Western diet (WD) and a low-carbohydrate, high-fat diet (LCHDF). Obesity was induced in 8-week-old C57BL/6 male mice by 10 weeks of WD feeding. Then, the mice were subjected to 12 weeks of LCHFD interspersed with WD (I-WD), 3 periods of 2-week LCHFD followed by 2 periods of 3-week WD, or 12 weeks of continuous WD (C-WD). C-WD and I-WD mice were compared to standard diet (SD) mice. In the I-WD group, each LCHFD period decreased weight gain, but mice regained weight after WD resumption. I-WD mice exhibited obesity, dyslipidemia, and glucose intolerance, similarly to the C-WD mice. I-WD mice also developed nonalcoholic steatohepatitis, associated with an increase in type-III collagen gene expression and a decrease in FGF21 protein levels, in comparison with SD. I-WD mice developed weight cycling despite maintaining a high caloric consumption, suggesting that changes in macronutrients during dieting are also a trigger of weight regain.

Obesity is associated with a low-grade inflammation, characterized by the secretion of inflammatory mediators, that contribute to non-alcoholic fatty liver disease (NAFLD) development. Steatosis may be complicated by hepatocellular injury and liver inflammation (steatohepatitis or NASH). Ketogenic diet (KD), a high-fat and low-carbohydrate diet, seems to present anti-inflammatory properties which could reduce NAFLD development. However, the mechanisms involved in its beneficial effects remain unclear. Obesity was induced in C57/Bl6 mice (n = 20) by using a high-fat, high-sugar diet (HFD). After 16 weeks of HFD, mice were split into two groups for six weeks: KD mice (n = 10) and HFD mice (n = 10). At the end of the 22-week protocol, we measured liver weight, hepatic lipid accumulation and inflammatory infiltrates with histological staining, and hepatic gene expression by RT-qPCR. Both HFD and KD were isocaloric and compared with a control diet (Ctrl) group of mice (n = 10). After 22 weeks of HFD, mice developed obesity (+82% of weight gain, p < 0.001) associated with an increase in liver weight (+113%, p < 0.001) and hepatic lipid accumulation (+158%, p < 0.001), compared with Ctrl. RT-qPCR revealed an increase in TNFa (p < 0.05), IL-1 (p < 0.05) and collagen 1 (p < 0.01) gene expression, but no changes of IL-10, TGFb and IFNg, compared to Ctrl. Histological staining showed an important steatosis and inflammatory infiltrates. Compared to HFD, six weeks of KD allow to reduce the liver weight (−31%, p < 0.01), reduce steatosis and ballooning hepatocytes, and decreased IL-6 (p < 0.05) and collagen 1 (p < 0.05) gene expression. However, KD had no effect on IL-1, TNFa, IFNg, IL-10 gene expression, compared to HFD. These results suggest that in a context of hypercaloric diet and NAFLD development, replacing sugar by lipids is efficient to prevent the onset of NASH at least partly due to a reduction in lipid accumulation and hepatocellular injuries.

Aim: We aimed to evaluate an innovative dose–response approach to assess the metaboreflex with control of intramuscular metabolic perturbation (concept of metaboreflex gain). We also investigated potential sex differences in the metaboreflex using this new approach. Methods: Thirty participants (15 females) completed one familiarization and two experimental visits to evaluate the method and assess its reproducibility. Each visit involved four consecutive bouts of sustained isometric knee extension at 20% of maximal voluntary force interspersed with 2 min of post‐exercise circulatory occlusion (PECO). Intramuscular metabolic perturbation was quantified indirectly via changes in quadriceps twitch force evoked by electrical stimulation of the femoral nerve (∆Q _TW ). Metaboreflex gain was calculated as the ratio of ∆mean arterial pressure (∆MAP) during PECO to ∆Q _TW . Results: We found a gradual increase in ∆MAP ( p < 0.0001) that was linearly correlated with the gradual decrease in ∆Q _TW ( p < 0.0001) during the exercise bouts ( r ² = 0.93; p = 0.037). Bland–Altman analysis showed a mean bias of 0.3 ± 0.5 for metaboreflex gain. Males exhibited greater metaboreflex to PECO than females when assessed “classically” with no control of ∆Q _TW (∆MAP; 49.1% ± 17.9% vs. 36.5% ± 8.7%; p = 0.020), whereas there was no sex difference when assessed using the metaboreflex gain (∆MAP/∆Q _TW ; 1.3 ± 0.6 vs. 1.8 ± 1.3; p = 0.325). The metaboreflex gain was not consistent across exercise bouts, showing that contrasting conclusions might emerge between two single assessments performed at different levels of metaboreflex activation. Conclusion: This study highlights the critical need for using a dose–response relationship while accounting for neuromuscular fatigue as a proxy for the metabolic stimulus when assessing the muscle metaboreflex in humans. Trial Registration: Clinical trials registration number: NCT06775119