Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle

Abstract

Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impaired muscle function in long-term survivors. However, no comprehensive assessment of skeletal muscle mitochondrial functions in long-term survivors has been performed and the presence of persistent chemotherapy-induced skeletal muscle mitochondrial dysfunction remains a strong possibility. Non-tumour-bearing mice were treated with two drugs that have been used frequently in ALL treatment (doxorubicin and dexamethasone) for up to 4 cycles at 3-week intervals and euthanized 3 months after the 4th cycle. Treated animals had impaired growth and lower muscle mass as well as reduced mitochondrial respiration and increased reactive oxygen species production per unit oxygen consumption. Mitochondrial DNA content and protein levels of key mitochondrial membrane proteins and markers of mitochondrial biogenesis were unchanged, but protein levels of Parkin were reduced. This suggests a novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling. The results could explain the observed functional impairments in adult survivors of childhood ALL and may also be relevant to long-term survivors of other cancers treated with similar regimes.

Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction

“…Following doxorubicin administration, soleus mitochondrial NADH-and FADH 2 -supported respiratory capacity is diminished. These findings are consistent with our previous work and other groups demonstrating that doxorubicin causes skeletal muscle mitochondrial dysfunction in a time-dependent manner (12,17,26).…”

“…Our current findings and the work of others (26) indicate that mitochondrial-targeted antioxidants may be an effective adjunct therapeutic approach for cancer patients undergoing chemotherapy to help prevent muscle weakness and loss. The reduction in muscle mass and function is both an acute and long-term problem for cancer patients (17,19), and thus limiting these distressing side effects could lead to improved therapy retention rates and enhanced quality of life for patients long term.…”

BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice

“…In skeletal muscle, this correlates with sustained dysfunction resulting in fatigue and wasting (Mantovani et al, 2003; Gilliam and St Clair, 2011; Gilliam et al, 2012; Gouspillou et al, 2015), with wasting being traditionally attributed to an imbalance between protein degradation and synthesis (Sandri, 2008). Since a decline in muscle mass is negatively associated with patient survivability, quality of life and chemotherapeutic treatment options (Talvensaari et al, 1996; Oeffinger et al, 2006; van Brussel et al, 2006; Ness et al, 2007, 2012; Scheede-Bergdahl and Jagoe, 2013), methods to protect the skeletal muscle from dysfunction and loss is of paramount importance.…”

“…Chemotherapy-induced oxidative stress has previously been linked, albeit almost exclusively following anthracycline treatment (Gilliam et al, 2012; Gouspillou et al, 2015), to mitochondrial-mediated cell damage pathways within skeletal muscle (Davies and Doroshow, 1986; Doroshow and Davies, 1986; Gilliam et al, 2012; Min et al, 2015). Since OXA, via the Pt component of the molecule, adducts nDNA resulting in DNA damage, impeded transcription/translation and cell death (Raymond et al, 1998; André et al, 2004; Gourdier et al, 2004; Alcindor and Beauger, 2011), we have previously hypothesized that OXA could induce the same damage to mtDNA (Sorensen et al, 2016).…”

Effects of Cobalt Chloride, a Hypoxia-Mimetic Agent, on Autophagy and Atrophy in Skeletal C2C12 Myotubes

“…Parkin is the central ubiquitin ligase to autophagy pathways [23]. Interestingly, an autophagy deficiency in denervated slow-twitch soleus muscles delayed skeletal muscle atrophy and reduced mitochondrial activity and parkin expression [24].…”