Inhibition of skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity

Shahtout, J. L.; Eshima, H.; Ferrara, P. J.; Maschek, J. A.; Cox, J. E.; Drummond, M. J.; Funai, K.

doi:10.1101/2023.07.25.550576

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bioRxiv · 10.1101/2023.07.25.550576

Inhibition of skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity

Shahtout, J. L.·Eshima, H.·Ferrara, P. J.·Maschek, J. A.·Cox, J. E.·Drummond, M. J.·Funai, K.

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Abstract

BackgroundLipid hydroperoxides (LOOH) have been implicated in skeletal muscle atrophy with age and disuse. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme of Lands cycle, conjugates a polyunsaturated fatty acyl chain to a lysophospholipid (PUFA-PL) molecule, providing substrates for LOOH propagation. Previous studies suggest that inhibition of Lands cycle is an effective strategy to suppress LOOH. Mice with skeletal muscle-specific tamoxifen-inducible knockout of LPCAT3 (LPCAT3-MKO) were utilized to determine if muscle-specific attenuation of LOOH may alleviate muscle atrophy and weakness with disuse. MethodsLPCAT3-MKO and control mice underwent 7 days of sham or hindlimb unloading (HU model) to study muscle mass and force-generating capacity. LOOH was assessed by quantifying 4-hydroxynonenal (4-HNE)-conjugated peptides. Quantitative PCR and lipid mass spectrometry were used to validate LPCAT3 deletion. Results7 days of HU was sufficient to induce muscle atrophy and weakness concomitant to an increase in 4-HNE. Deletion of LPCAT3 reversed HU-induced increase in muscle 4HNE. No difference was found in body mass, body composition, or caloric intake between genotypes. The soleus (SOL) and plantaris (PLANT) muscles of the LPCAT3-MKO mice were partially protected from atrophy compared to controls, concomitant to attenuated decrease in cross-sectional areas in type I and IIa fibers. Strikingly, SOL and extensor digitorum longus (EDL) were robustly protected from HU-induced reduction in force-generating capacity in the LPCAT3-MKO mice compared to controls. ConclusionOur findings demonstrate that attenuation of muscle LOOH is sufficient to restore skeletal muscle function, in particular a protection from reduction in muscle specific force. Thus, muscle LOOH contributes to atrophy and weakness induced by HU in mice.

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Shahtout, J. L., Eshima, H., Ferrara, P. J., Maschek, J. A., Cox, J. E., Drummond, M. J., Funai, K.. 2023-07-28. Inhibition of skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity. https://doi.org/10.1101/2023.07.25.550576

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