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Baelde 2023 Abstract IOC160

From Bioblast
Baelde R, Fortes Monteiro A, Nollet E, Galli R, Strom J, van der Velden J, Ottenheijm C, de Winter J (2023) Kbtbd13R408C-knockin mouse model elucidates mitochondrial pathomechanism in NEM6. Mitochondr Physiol Network 28.01.

Link: IOC160

Baelde Rianne, Fortes Monteiro Alexica, Nollet Edgar, Galli Ricardo, Strom Joshua, van der Velden Jolanda, Ottenheijm Coen, de Winter Josine (2023)

Event: IOC160

Nemaline Myopathy (NEM) is among the most common non-dystrophic congenital myopathies. Nemaline Myopathy type 6 (NEM6) is characterized by muscle weakness and muscle slowness and caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbors the Dutch founder mutation KBTBD13R408C (c.1222C>T, p.Arg408Cys). Histological characterization of NEM6 patient biopsies by NADH staining showed the presence of cores, indicating the absence of complex I (NADH) activity, suggesting mitochondrial dysfunction. Here, we aimed to investigate whether mitochondrial dysfunction contributes to NEM6 disease pathology. Therefore, we used the Kbtbd13R408C-knockin mouse model that phenocopies NEM6 hallmarks, e.g muscle weakness, impaired muscle relaxation kinetics and the presence of nemaline bodies. First, we used metabolic treadmill experiments to investigate mitochondrial function in vivo. 9 months old homozygous Kbtbd13R408C-knockin mice showed a significant impaired running performance, decreased VO2max and increased respiratory exchange ratio (RER) compared to wildtype (WT) mice. Second, mitochondrial respiration was investigated at the muscle tissue level by in vitro respirometry experiments in oxidative muscle (soleus). Soleus muscle of Kbtbd13R408C-knockin mice showed significant decreased complex I (NADH) linked respiration and total oxidative phosphorylation compared to WT mice, indicating that mitochondrial dysfunction contributes to the lower VO2max and running performance assessed in vivo. Third, we performed enzymatic NADH and SDH stainings on cryosections of soleus muscle of 9 months old WT and Kbtbd13R408C-knockin mice to assess enzymatic activity in both slow-twitch (type I) and intermediate/fast-twitch (type IIa) myofibers. Soleus muscle of Kbtbd13R408C- knockin mice showed cores in both type I and type IIa myofibers.

To conclude, the presence of cores in myofibers of Kbtbd13R408C-knockin mice phenocopies NEM6 patients. The Kbtbd13R408C-knockin mouse model revealed that mitochondrial dysfunction contributes to NEM6 disease pathology. Next, we will use the Kbtbd13R408C-knockin mouse model to study the onset and progression of mitochondrial dysfunction in NEM6 and test interventions that target mitochondrial function.

โ€ข Bioblast editor: Plangger M โ€ข O2k-Network Lab: NL Amsterdam Nollet E

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Myopathy 

Organism: Mouse 

HRR: Oxygraph-2k 


Rianne Baelde1, Alexcia Fortes Monteiro1, Edgar Nollet1, Ricardo Galli1, Joshua Strom2, Jolanda van der Velden1, Coen Ottenheijm1, Josine de Winter1
  1. Dept of Physiology, Amsterdam UMC, location VUmc, The Netherlands
  2. Dept of Cellular and Molecular Medicine, University of Arizona, Tucson, USA