Key result
Recessive Ryr1 mutations in mice significantly decreased RyR1 protein content and broadly altered the expression of proteins involved in excitation-contraction coupling, extracellular matrix, and heat shock response, particularly in fast-twitch and extraocular muscles.
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Level 5 human-animal data on muscle heterogeneity in congenital myopathies leaves open clinical relevance; targeted trials required before practice impact.
Skeletal muscle is a highly structured and differentiated tissue responsible for voluntary movement and metabolic regulation. Muscles however, are heterogeneous and depending on their location, speed of contraction, fatiguability and function, can be broadly subdivided into fast and slow twitch as well as subspecialized muscles, with each group expressing common as well as specific proteins. Congenital myopathies are a group of non-inflammatory non-dystrophic muscle diseases caused by mutations in a number of genes, leading to a weak muscle phenotype. In most cases specific muscles types are affected, with preferential involvement of fast twitch muscles as well as extraocular and facial muscles. Here we performed relative and absolute quantitative proteomic analysis of EDL, soleus and extraocular muscles from wild type and transgenic mice carrying compound heterozygous mutations in Ryr1 identified in a patient with a severe congenital myopathy. Our quantitative proteomic study shows that recessive Ryr1 mutations not only decrease the content of RyR1 protein in muscle, but also impact the content of many other proteins; in addition, we provide important insight into the pathological mechanism of congenital myopathies linked to mutations in other genes encoding components of the excitation contraction coupling molecular complex.
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Eckhardt et al. (2022) studied Congenital myopathies (n=10). Ryr1 compound heterozygous mutations vs. Wild type mice was evaluated on Quantitative proteomic changes in skeletal muscles (EDL, soleus, EOM). Recessive Ryr1 mutations in mice significantly decreased RyR1 protein content and broadly altered the expression of proteins involved in excitation-contraction coupling, extracellular matrix, and heat shock response, particularly in fast-twitch and extraocular muscles.
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