Autologous mitochondrial transplantation in male mice as a strategy to prevent deleterious effects of peripheral ischemia-reperfusion.

Ischemia-reperfusion (IR) is known to induce severe tissue damage, notably through mitochondrial dysfunction. Mitochondrial transplantation has emerged as a promising therapeutic strategy in cardiac IR; however, few studies have previously assessed its efficacy in the context of peripheral IR. Therefore, the objective of this study was to assess the effect of mitochondrial transplantation in a hindlimb model of IR injury. Thirty-six SWISS mice were divided into three groups: control (CTL, n = 12), ischemia-reperfusion (IR, n = 12), and IR with mitochondrial transplantation (MT, n = 12). Ischemia (2 h) was induced using the tourniquet model around the right hind limb in the IR and MT groups. In MT group, mitochondria isolated from the right rectus muscle, a nonischemic region, were injected shortly before reperfusion. Mitochondrial respiration, calcium retention capacity, and Western blotting analysis were performed 2 h after reperfusion. Compared with the CTL group, IR led to a decrease in the mitochondrial respiratory capacity, particularly for the basal state (-30%; P = 0.015), oxidative phosphorylation (-36%; P = 0.024), and calcium retention capacity (-45%; P = 0.007). Interestingly, mitochondrial transplantation partially restored these functions since no differences between MT and CTL groups were found. In addition, the administration of healthy mitochondria resulted in a positive regulation of redox balance and mitochondrial dynamics within the skeletal muscle. Although further investigations are needed to better characterize underlying mechanisms, mitochondrial transplantation represents a promising strategy in the setting of IR-induced muscular damage.NEW & NOTEWORTHY 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.

A single chemotherapy administration induces muscle atrophy, mitochondrial alterations and apoptosis in breast cancer patients.

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 H2 O2 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 H2 O2 production.