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Murphy 2016 Abstract FASEB J

From Bioblast
Metformin limits loss of mitochondrial respiration seen with doxorubicin treatment without affecting muscle function.

Link: FASEB Link

Murphy ST, Crandall AD, Louw MJ, Bernhisel D, Reynolds M, Hancock CR (2016)


Doxorubicin (DOX) is a commonly-used chemotherapeutic drug with a well characterized side effect of skeletal muscle wasting and weakness. It has been shown that DOX contributes to skeletal muscle damage through increasing oxidative stress. It has been suggested that this is due to DOX reacting with free cellular iron which then catalyzes the production of reactive oxygen species (ROS). ROS contribute to cell damage and dysfunction, and thus may play a role in the skeletal muscle wasting seen with DOX treatment. Recent work has shown that Metformin (MET) may protect against this oxidative environment by increasing iron storage capacity, thus preventing skeletal muscle wasting. We hypothesized that mice treated with DOX would see decreased muscle function and decreased respiratory capacity, and that pretreatment with MET would ameliorate these negative side effects. Male C57BL/6 mice were randomly placed into three groups: control, DOX or MET+DOX. Control mice received five doses of saline orally for five days before sacrifice, and one dose of saline intraperitoneally three days before sacrifice. DOX mice received one dose of DOX at 15 mg/kg three days before sacrifice. MET+DOX mice were given MET at 500 mg/kg two days before DOX treatment at 15 mg/kg. They were given this same dosage of MET every day until they were sacrificed three days after DOX treatment. Muscle function was measured in the gastrocnemius, plantaris and soleus muscle complex in situ, with mice under anesthesia (100 msec tetanic contractions at 0.5 Hz for 6 min). Mitochondrial respiratory function was measured in permeabilized fiber bundles from red gastrocnemius muscle using high-resolution respirometry (Oroboros Oxygraph-2k). Treatment with DOX resulted in a 16.0–20.2% reduction in overall body weight in both the DOX and MET+DOX groups as compared to control (p-value < 0.001). The weight difference between DOX and MET+DOX groups was not significant. Compared to control, DOX treatment caused a reduction in complex I stimulated, complex II stimulated, and uncoupled respiration (20–60% with p-value < 0.001). MET significantly prevented these reductions (i.e. max uncoupled respiration was 81% of control with p-value 0.08). Surprisingly we saw no significant differences in absolute force, twitch force, half relaxation time, or muscle fatigue between any of the three groups. These findings show that pretreatment with MET prevents decreases in mitochondrial respiration caused by DOX, but may not prevent muscle wasting. More research is needed in this area to find treatment options for DOX-induced skeletal muscle dysfunction.

This abstract is from the Experimental Biology 2016 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

β€’ O2k-Network Lab: US UT Provo Hancock CR

Labels: MiParea: Respiration, Exercise physiology;nutrition;life style, Pharmacology;toxicology 

Stress:Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: ET  Pathway: N, S  HRR: Oxygraph-2k 

2016-07, Metformin