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Published on: September 18, 2019
Nox2 signaling and muscle fiber remodeling are attenuated by losartan administration during skeletal muscle unloading
Jeffrey M Hord1, Marcela M Garcia1, Katherine R Farris1
1Redox Biology & Cell Signaling Laboratory, Department of Health and Kinesiology, Graduate Faculty of Nutrition, Texas A&M University, College Station, TX, USA.
Abstract:
Reduced mechanical loading results in atrophy of skeletal muscle fibers. Increased reactive oxygen species (ROS) are causal in sarcolemmal dislocation of nNOS and FoxO3a activation. The Nox2 isoform of NADPH oxidase and mitochondria release ROS during disuse in skeletal muscle. Activation of the angiotensin II type 1 receptor (AT1R) can elicit Nox2 complex formation. The AT1R blocker losartan was used to test the hypothesis that AT1R activation drives Nox2 assembly, nNOS dislocation, FoxO3a activation, and thus alterations in morphology in the unloaded rat soleus. Male Fischer 344 rats were divided into four groups: ambulatory control (CON), ambulatory + losartan (40 mg kg-1 day-1 ) (CONL), 7 days of tail-traction hindlimb unloading (HU), and HU + losartan (HUL). Losartan attenuated unloading-induced loss of muscle fiber cross-sectional area (CSA) and fiber-type shift. Losartan mitigated unloading-induced elevation of ROS levels and upregulation of Nox2. Furthermore, AT1R blockade abrogated nNOS dislocation away from the sarcolemma and elevation of nuclear FoxO3a. We conclude that AT1R blockade attenuates disuse remodeling by inhibiting Nox2, thereby lessening nNOS dislocation and activation of FoxO3a.
Insights
Losartan, an AT1R blocker, prevents skeletal muscle atrophy during unloading by inhibiting Nox2, reducing reactive oxygen species (ROS), and preserving muscle fiber structure.
Area of Science:
- Muscle physiology
- Cellular biology
- Biochemistry
Background:
- Reduced mechanical loading causes skeletal muscle atrophy.
- Reactive oxygen species (ROS) mediate sarcolemmal nNOS dislocation and FoxO3a activation during muscle unloading.
- Nox2 NADPH oxidase and mitochondria are key sources of ROS in disused skeletal muscle.
Purpose of the Study:
- To investigate if AT1R activation drives Nox2 assembly, nNOS dislocation, FoxO3a activation, and muscle atrophy in unloaded rat soleus.
- To test the efficacy of the AT1R blocker losartan in preventing these disuse-induced changes.
Main Methods:
- Male Fischer 344 rats were subjected to 7 days of hindlimb unloading (HU) with or without losartan treatment.
- Groups included: control (CON), control + losartan (CONL), HU, and HU + losartan (HUL).
- Muscle fiber cross-sectional area (CSA), fiber type, ROS levels, Nox2 expression, nNOS localization, and nuclear FoxO3a were assessed.
Main Results:
- Losartan attenuated unloading-induced loss of muscle fiber CSA and prevented fiber type shifts.
- Losartan mitigated the increase in ROS levels and Nox2 expression caused by unloading.
- AT1R blockade prevented nNOS dislocation and the elevation of nuclear FoxO3a.
Conclusions:
- AT1R blockade attenuates disuse-induced skeletal muscle remodeling.
- Inhibition of Nox2 by losartan reduces ROS production, nNOS dislocation, and FoxO3a activation during muscle unloading.
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