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

Tinklenberg, J.; Slick, Rebecca A.; Sutton, J. R.; Zhang, Liwen; Meng, Hui; Beatka, Margaret; Avond, Mark A. Vanden; Prom, Mariah J.; Ott, Emily; Montanaro, Federica; Heisner, James S.; Toro, R.; Hardeman, Edna C.; Geurts, Aron M.; Stowe, David F.; Hill, Rolla B.; Lawlor, Michael W.

doi:10.1016/j.ajpath.2023.06.008

Cited by 4 publications

(2 citation statements)

References 34 publications

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“…Interestingly, when clustering the 273 targets that are differentially regulated (according to their biological families), many proteins related to ATP synthesis, glucose metabolism, lipid metabolism, mitochondrial morphogenesis, organisation and function are significantly different. As this metabolic reprogramming is not affected by the drug administration in c Neb KO mice, we speculate that the damages observed to metabolic proteins, organelles and/or related signalling pathways in this mouse model (Ranu et al ., 2022; Tinklenberg et al ., 2023) are not reversible, at least in the short term. Further studies are warranted.…”

Section: Discussionmentioning

confidence: 99%

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle

Laitila,

Seaborne,

Ranu

et al. 2024

Preprint

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Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. As the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, here, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP over-consumption. Following this, we assessed its short-term in vivo effects by using the conditional nebulin knock-out (cNeb KO) mouse model and by subsequently performing global proteomics profiling in dissected soleus myofibres. After a four-week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo.

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Section: Discussionmentioning

confidence: 99%

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle

Laitila,

Seaborne,

Ranu

et al. 2024

Preprint

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“…Interestingly, actin regulates cytochrome c retention between respiratory chain complexes III and IV in brain mitochondria via direct association with both complexes, and inhibition of actin polymerization with cytochalasin b increased mitochondrial respiration via increased complex IV activity [82]. Recently, proteomic analysis using NEB [83] and ACTA1 [84] mouse models showed alterations in several cellular processes and functions, including mitochondrial dysfunction and changes in energetic metabolism and stress-related pathways. Abnormal mitochondrial distribution, reduced mitochondrial respiratory function, increased mitochondrial membrane potential, and abnormally low ATP content were all revealed by structural and functional studies.…”

Section: Discussionmentioning

confidence: 99%

Actin Polymerization Defects Induce Mitochondrial Dysfunction in Cellular Models of Nemaline Myopathies

Piñero-Pérez,

López-Cabrera,

Álvarez-Córdoba

et al. 2023

Antioxidants

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Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and it is identified by the presence of “nemaline bodies” (rods) in muscle fibers by histopathological examination. The most common forms of NM are caused by mutations in the Actin Alpha 1 (ACTA1) and Nebulin (NEB) genes. Clinical features include hypotonia and muscle weakness. Unfortunately, there is no curative treatment and the pathogenetic mechanisms remain unclear. In this manuscript, we examined the pathophysiological alterations in NM using dermal fibroblasts derived from patients with mutations in ACTA1 and NEB genes. Patients’ fibroblasts were stained with rhodamine–phalloidin to analyze the polymerization of actin filaments by fluorescence microscopy. We found that patients’ fibroblasts showed incorrect actin filament polymerization compared to control fibroblasts. Actin filament polymerization defects were associated with mitochondrial dysfunction. Furthermore, we identified two mitochondrial-boosting compounds, linoleic acid (LA) and L-carnitine (LCAR), that improved the formation of actin filaments in mutant fibroblasts and corrected mitochondrial bioenergetics. Our results indicate that cellular models can be useful to study the pathophysiological mechanisms involved in NM and to find new potential therapies. Furthermore, targeting mitochondrial dysfunction with LA and LCAR can revert the pathological alterations in NM cellular models.

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Aberrations in Energetic Metabolism and Stress-Related Pathways Contribute to Pathophysiology in the Neb Conditional Knockout Mouse Model of Nemaline Myopathy

Slick

Tinklenberg

Sutton³

et al. 2023

The American Journal of Pathology

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

Cited by 4 publications

References 34 publications

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle

Actin Polymerization Defects Induce Mitochondrial Dysfunction in Cellular Models of Nemaline Myopathies

Aberrations in Energetic Metabolism and Stress-Related Pathways Contribute to Pathophysiology in the Neb Conditional Knockout Mouse Model of Nemaline Myopathy

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