Phosphatidylserine decarboxylase is critical for the maintenance of skeletal muscle mitochondrial integrity and muscle mass

Abstract

Objective Phosphatidylethanolamine (PtdEtn) is a major phospholipid in mammals. It is synthesized via two pathways, the CDP-ethanolamine pathway in the endoplasmic reticulum and the phosphatidylserine (PtdSer) decarboxylase (PSD) pathway in the mitochondria. While the CDP-ethanolamine pathway is considered the major route for PtdEtn synthesis in most mammalian tissues, little is known about the importance of the PSD pathway in vivo, especially in tissues enriched with mitochondria such as skeletal muscle. Therefore, we aimed to examine the role of the mitochondrial PSD pathway in regulating PtdEtn homeostasis in skeletal muscle in vivo . Methods To determine the functional significance of this pathway in skeletal muscle in vivo , an adeno-associated viral vector approach was employed to knockdown PSD expression in skeletal muscle of adult mice. Muscle lipid and metabolite profiling was performed using mass spectrometry. Results PSD knockdown disrupted muscle phospholipid homeostasis leading to an ∼25% reduction in PtdEtn and an ∼45% increase in PtdSer content. This was accompanied by the development of a severe myopathy, evident by a 40% loss in muscle mass as well as extensive myofiber damage as shown by increased DNA synthesis and central nucleation. In addition, PSD knockdown caused marked accumulation of abnormally appearing mitochondria that exhibited severely disrupted inner membrane integrity and reduced OXPHOS protein content. Conclusions The PSD pathway has a significant role in maintaining phospholipid homeostasis in adult skeletal muscle. Moreover, PSD is essential for maintenance of mitochondrial integrity and skeletal muscle mass.

Older adults with sarcopenia have distinct skeletal muscle phosphodiester, phosphocreatine, and phospholipid profiles

“…The changes in phospholipid composition were associated with reduced type IIb myofiber size in aged muscle (Uchitomi et al, 2019), which is similar to our findings revealing a negative association between phospholipids (PC, PE, and PG) with muscle volume. While in contrast to recent reports that showed reducing PE levels in skeletal muscle by inhibiting key phospholipid synthesis pathways (phosphatidylserine decarboxylase) results in muscle atrophy (Heden et al, 2019; Selathurai et al, 2019), our findings and those by Uchitomi et al (2019) reveal that age‐induced muscle atrophy may be linked to elevated phospholipids levels in skeletal muscle.…”

Circulating Mitochondrial-Derived Vesicles, Inflammatory Biomarkers and Amino Acids in Older Adults With Physical Frailty and Sarcopenia: A Preliminary BIOSPHERE Multi-Marker Study Using Sequential and Orthogonalized Covariance Selection – Linear Discriminant Analysis

“…Phosphoethanolamine is an ethanolamine derivate produced as an intermediate of the CDP-ethanolamine pathway involved in the metabolism of glycerophospholipid and biological membrane turnover (Patel and Witt, 2017 ; van der Veen et al, 2017 ). Disruption of CDP-ethanolamine pathway has been associated with mitochondrial dyshomeostasis in mouse models of muscle atrophy (Selathurai et al, 2019 ) and insulin resistance (Funai et al, 2016 ). Phosphoethanolamine has also been found to mediate mitochondrial membrane fusion and curvatures and, in combination with ethanolamine, to promote autophagy and longevity (Rockenfeller et al, 2015 ).…”

Doxorubicin Inhibits Phosphatidylserine Decarboxylase and Modifies Mitochondrial Membrane Composition in HeLa Cells

“…Tasseva et al reported a reduced mitochondrial pool of PE in CHO PISD knockdown cells, characterized by a fragmented mitochondrial network [12]. Furthermore, PSD knockdown expression in the skeletal muscle of mice was responsible for the decrease in PE content and rise in PS with myopathy development [16]. Therefore, we hypothesized that PSD could play a role in the proposed mitochondrial membrane effects of DXR.…”