Exercise, but Not Metformin Prevents Loss of Muscle Function Due to Doxorubicin in Mice Using an In Situ Method.

Though effective in treating various types of cancer, the chemotherapeutic doxorubicin (DOX) is associated with skeletal muscle wasting and fatigue. The purpose of this study was to assess muscle function in situ following DOX administration in mice. Furthermore, pre-treatments with exercise (EX) or metformin (MET) were used in an attempt to preserve muscle function following DOX. Mice were assigned to the following groups: control, DOX, DOX + EX, or DOX + MET, and were given a single injection of DOX (15 mg/kg) or saline 3 days prior to sacrifice. Preceding the DOX injection, DOX + EX mice performed 60 min/day of running for 5 days, while DOX + MET mice received 5 daily oral doses of 500 mg/kg MET. Gastrocnemius-plantaris-soleus complex function was assessed in situ via direct stimulation of the sciatic nerve. DOX treatment increased time to half-relaxation following contractions, indicating impaired recovery (p < 0.05). Interestingly, EX prevented any increase in half-relaxation time, while MET did not. An impaired relaxation rate was associated with a reduction in SERCA1 protein content (p = 0.07) and AMPK phosphorylation (p < 0.05). There were no differences between groups in force production or mitochondrial respiration. These results suggest that EX, but not MET may be an effective strategy for the prevention of muscle fatigue following DOX administration in mice.

Multitissue analysis of exercise and metformin on doxorubicin-induced iron dysregulation.

Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting side effects in heart and skeletal muscle. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, major cellular changes to iron regulation in response to DOX are poorly understood in liver, heart, and skeletal muscle. Additionally, two cotreatments, exercise (EX) and metformin (MET), were studied for their effectiveness in reducing DOX toxicity by ameliorating iron dysregulation and preventing oxidative stress. The purposes of this study were to 1) characterize the DOX-induced changes of the major iron regulation pathway in liver, heart, and skeletal muscle and 2) to determine whether EX and MET exert their benefits by minimizing DOX-induced iron dysregulation. Mice were assigned to receive saline or DOX (15 mg/kg) treatments, paired with either EX (5 days) or MET (500 mg/kg), and were euthanized 3 days after DOX treatment. Results suggest that the cellular response to DOX is protective against oxidative stress by reducing iron availability. DOX increased iron storage capacity through elevated ferritin levels in liver, heart, and skeletal muscle. DOX reduced iron transport capacity through reduced transferrin receptor levels in heart and skeletal muscle. EX and MET cotreatments had protective effects in the liver through reduced transferrin receptor levels. At 3 days after DOX, oxidative stress was mild, as shown by normal glutathione and lipid peroxidation levels. Together these results suggest that the cellular response to reduce iron availability in response to DOX treatment is sufficient to match oxidative stress.

MRI characteristics of suspected acute spinal cord infarction in two cats, and a review of the literature.

A 10-year-old neutered male Persian cat and a 4-year-old spayed female domestic shorthair (DSH) cat were evaluated for acute-onset severe lateralising tetraparesis and hemiplegia, respectively. Both cats also had left-sided Horner's syndrome. Neurological examination of the cats localised the lesion to cranial to C5 in the Persian and the left cervical intumescence (C6-T2) in the DSH. Physical examinations were otherwise generally unremarkable. Routine laboratory tests and spinal radiography were normal for the Persian cat and were not performed for the DSH cat. A cerebrospinal fluid (CSF) tap was attempted for the Persian cat but aborted because of gross blood contamination, and was not performed for the DSH cat. Magnetic resonance imaging (MRI) of the Persian cat revealed a lesion within the spinal parenchyma at segments C1 to C3 (slightly more left-sided) which was iso- to hypointense on T1-weighted scans and hyperintense on T2-weighted scans, and which enhanced slightly with gadolinium. MRI of the DSH cat revealed a lesion within the spinal parenchyma at segment C7 (predominantly left-sided) which was hypointense on T1-weighted scans and hyperintense on T2-weighted gradient echo scans. Contrast was not administered. The MRI findings in both cases were highly suggestive of acute spinal cord infarction, based upon comparison to human cases. Both cats made full neurological recoveries with supportive treatment only. This paper describes two cases of suspected acute spinal cord infarction in the cat, demonstrates the potential diagnostic value of MRI, and discusses the clinical syndrome of this condition with a brief review of published cases.