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

Abstract

Lipid 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. LPCAT3-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. 7 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. Our 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.

Lipid peroxidation does not mediate muscle atrophy induced by PSD deficiency

“…Global or muscle-specific suppression of LOOH was sufficient to prevent accumulation of LOOH in skeletal muscle and protected muscles from disuse-induced muscle atrophy [2,[4][5][6][7]. Together with findings from the current study that GPx4 overexpression does not rescue muscle atrophy in PSD-MKO mice, we can interpret that LOOH drives muscle atrophy with hindlimb unloading but not with PSD deficiency.…”

“…Suppression of muscle LOOH by overexpression of glutathione peroxidase 4 (GPx4) [3], a phospholipid peroxidase, was sufficient to partly rescue the loss of muscle mass induced by hindlimb unloading. Other findings from are consistent with the notion that lipid ROS may mediate the skeletal muscle atrophy induced by physical activity [4][5][6][7].…”