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Am J Pathol. 2014 Jan;184(1):248-59. doi: 10.1016/j.ajpath.2013.09.009. Epub 2013 Oct 29.

Dysferlin and myoferlin regulate transverse tubule formation and glycerol sensitivity.

Author information

1
Department of Medicine, The University of Chicago, Chicago, Illinois.
2
Department of Pathology, The University of Chicago, Chicago, Illinois.
3
Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida.
4
Department of Medicine, The University of Chicago, Chicago, Illinois; Department of Human Genetics, The University of Chicago, Chicago, Illinois. Electronic address: emcnally@uchicago.edu.

Abstract

Dysferlin is a membrane-associated protein implicated in muscular dystrophy and vesicle movement and function in muscles. The precise role of dysferlin has been debated, partly because of the mild phenotype in dysferlin-null mice (Dysf). We bred Dysf mice to mice lacking myoferlin (MKO) to generate mice lacking both myoferlin and dysferlin (FER). FER animals displayed progressive muscle damage with myofiber necrosis, internalized nuclei, and, at older ages, chronic remodeling and increasing creatine kinase levels. These changes were most prominent in proximal limb and trunk muscles and were more severe than in Dysf mice. Consistently, FER animals had reduced ad libitum activity. Ultrastructural studies uncovered progressive dilation of the sarcoplasmic reticulum and ectopic and misaligned transverse tubules in FER skeletal muscle. FER muscle, and Dysf- and MKO-null muscle, exuded lipid, and serum glycerol levels were elevated in FER and Dysf mice. Glycerol injection into muscle is known to induce myopathy, and glycerol exposure promotes detachment of transverse tubules from the sarcoplasmic reticulum. Dysf, MKO, and FER muscles were highly susceptible to glycerol exposure in vitro, demonstrating a dysfunctional sarcotubule system, and in vivo glycerol exposure induced severe muscular dystrophy, especially in FER muscle. Together, these findings demonstrate the importance of dysferlin and myoferlin for transverse tubule function and in the genesis of muscular dystrophy.

PMID:
24177035
PMCID:
PMC3873498
DOI:
10.1016/j.ajpath.2013.09.009
[Indexed for MEDLINE]
Free PMC Article

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