Portman, K. | Search bioRxiv

bioRxiv2021

Deficiency of peroxisomal L-bifunctional protein (EHHADH) causes male-specific kidney hypertrophy and proximal tubular injury in mice

BackgroundProximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of peroxisomal metabolism remains largely unknown. EHHADH, also known as L-bifunctional protein, catalyzes the second and third step of peroxisomal FAO. MethodsWe studied kidneys of WT and Ehhadh KO mice using histology, immunohistochemistry, immunofluorescence, immunoblot, RNA-sequencing, metabolomics and orchiectomy. ResultsWe observed male-specific kidney hypertrophy and glomerular filtration rate reduction in adult Ehhadh KO mice. Transcriptome analysis unveiled a gene expression signature similar to PT injury in acute kidney injury mouse models. This was further illustrated by the presence of KIM-1 (kidney injury molecule-1), SOX-9, and Ki67-positive cells in the PT of male Ehhadh KO kidneys. Male Ehhadh KO kidneys had metabolite changes consistent with peroxisomal dysfunction as well as an elevation in glycosphingolipids levels. Orchiectomy of Ehhadh KO mice reversed kidney enlargement and decreased the number of KIM-1 positive cells. We reveal a pronounced sexual dimorphism in the expression of peroxisomal FAO proteins in mouse kidney, underlining a role of androgens in the kidney phenotype of Ehhadh KO mice. ConclusionsOur data highlight the importance of EHHADH and peroxisomal metabolism in male kidney physiology and reveal peroxisomal FAO as a sexual dimorphic metabolic pathway in mouse kidneys.

physiology↗

bioRxiv2020

Mitochondrial dysfunction in skeletal muscle of fukutin deficient mice is resistant to exercise- and AICAR-induced rescue

Disruptions in the dystrophin-glycoprotein complex (DGC) are clearly the primary basis underlying various forms of muscular dystrophies and dystroglycanopathies, but the cellular consequences of DGC disruption are still being investigated. Mitochondrial abnormalities are becoming an apparent consequence and contributor to dystrophy disease pathology. Herein, we demonstrate that muscle-specific deletion of the fukutin gene [Myf5/fktn-KO mice (KO)], a model of secondary dystroglycanopathy, results in ~30% lower muscle strength (P<0.001) and 16% lower mitochondrial function (P=0.002) compared to healthy littermate controls (LM). We also observed ~80% lower PGC-1 signaling (P=0.004), a primary transcription factor for mitochondrial biogenesis, in KO mice that likely contributes to the mitochondrial defects. PGC-1 is post-translationally regulated via phosphorylation by AMPK. Treatment with the AMPK agonist AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) failed to rescue mitochondrial deficits in KO mice (P=0.458) but did have beneficial (~30% greater) effects on recovery of muscle contractility following injury in both LM and KO mice compared to saline treatment (P=0.006). The beneficial effects of AMPK stimulation via AICAR on muscle function may be partially explained by AMPKs other role of regulating skeletal muscle autophagy, a cellular process critical for clearance of damaged and/or dysfunctional organelles. Two primary conclusions can be drawn from this data, 1) fukutin deletion produces intrinsic muscular metabolic defects that likely contribute to dystroglycanopathy disease pathology, and 2) AICAR treatment accelerates recovery of muscle function following injury suggesting AMPK signaling as a possible target for therapeutic strategies.

physiology↗