Dataset Information

Identifying secondary processes implicated in nemaline myopathy pathophysiology

ABSTRACT: Nemaline myopathy (NM) is a genetically and clinically heterogeneous disease that is diagnosed based on the presence of nemaline rods on skeletal muscle biopsy. While NM has typically been classified by causative genes, disease severity or prognosis cannot be predicted well. The common pathological endpoint of nemaline rods (despite diverse genetic causes) and an unexplained range of muscle weakness suggests that shared secondary processes contributed to the pathogenesis of NM. We speculated that these processes could be identified through a proteome wide interrogation utilizing a mouse model of severe NM in combination with pathway validation and structural/functional analyses. A proteomic analysis was performed using skeletal muscle tissue from the Neb cKO, KI.Acta1H40Y, and TgACTA1D286G mouse models of nemaline myopathy as compared to their respective wild-type counterparts (Neb WT, WT.Acta1H40Y, and C57) to identify pathophysiologically relevant biological processes that might impact disease severity or provide new treatment targets. Downstream analyses utilizing Scaffold, RStudio, and Ingenuity Pathway Analysis identified mitochondrial dysfunction and stress-related signaling as being enriched in NM mouse datasets. Pathway validation revealed that proteins in mitochondrial and stress-related signaling pathways aggregated in NM muscle in a severity dependent manner and an increase in protein content was generally associated with more severe disease. Structural and functional mitochondrial analyses revealed that mitochondrial dysfunction also grades with disease severity. RCI measured by respirometry, ATP/ADP/phosphate content, and mitochondrial transmembrane potential were affected in a severity dependent manner with the Neb cKOs being the most abnormal, KI.Acta1H40Y being mildly affected, and the TgACTA1D286G being minimally affected. These studies identify mitochondrial dysfunction as a secondary process impacting disease severity in NM.

INSTRUMENT(S): Orbitrap Fusion, Bruker Daltonics timsTOF series

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle

DISEASE(S): Nemaline Myopathy,Myopathy

SUBMITTER: Rebecca Slick

LAB HEAD: Michael William Lawlor

PROVIDER: PXD042201 | Pride | 2025-05-06

REPOSITORIES: Pride

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Different Mouse Models of Nemaline Myopathy Harboring Acta1 Mutations Display Differing Abnormalities Related to Mitochondrial Biology.

Tinklenberg Jennifer A JA Slick Rebecca A RA Sutton Jessica J Zhang Liwen L Meng Hui H Beatka Margaret J MJ Vanden Avond Mark M Prom Mariah J MJ Ott Emily E Montanaro Federica F Heisner James J Toro Rafael R Hardeman Edna C EC Geurts Aron M AM Stowe David F DF Hill R Blake RB Lawlor Michael W MW

The American journal of pathology 20230705 10

ACTA1 encodes skeletal muscle-specific α-actin, which polymerizes to form the thin filament of the sarcomere. Mutations in ACTA1 are responsible for approximately 30% of nemaline myopathy (NM) cases. Previous studies of weakness in NM have focused on muscle structure and contractility, but genetic issues alone do not explain the phenotypic heterogeneity observed in patients with NM or NM mouse models. To identify additional biological processes related to NM phenotypic severity, proteomic analys ...[more]

PMID: 37419385

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