Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice

Andrea A. Domenighetti, Pao Hsien Chu, Tongbin Wu, Farah Sheikh, David S. Gokhin, Ling T. Guo, Ziyou Cui, Angela K. Peter, Danos C. Christodoulou, Michael G. Parfenov, Joshua M. Gorham, Daniel Y. Li, Indroneal Banerjee, Xianyin Lai, Frank Witzmann, Christine E. Seidman, Jonathan G. Seidman, Aldrin V. Gomes, G. Diane Shelton, Richard L. LieberJu Chen

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in fourand- a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing bodymyopathy and Emery-Dreifuss muscular dystrophy. However, itremains tobe clarifiedwhethermutationsinFHL1 cause skeletalmuscleremodelingowingto gain- or loss of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss-offunction effects on skeletalmuscle homeostasis. Histological and functional analyses of soleus, tibialis anterior andsternohyoideusmusclesdemonstratedthatFHL1-nullmicedevelopanage-dependentmyopathyassociated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates inFHL1-nullmice,associatedwithage-dependentimpairmentofmusclecontractile functionanda significantly lower exercise capacity.Analysis of primarymyoblasts isolated fromFHL1-nullmusclesdemonstrated early muscle fiber differentiation and maturation defects,which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations.

Original languageEnglish
Article numberddt412
Pages (from-to)209-225
Number of pages17
JournalHuman Molecular Genetics
Volume23
Issue number1
DOIs
StatePublished - Jan 2014

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Muscular Diseases
Skeletal Muscle
Muscles
LIM Domain Proteins
Emery-Dreifuss Muscular Dystrophy
Myotonia Congenita
Medical Genetics
Sarcoplasmic Reticulum
Missense Mutation
Longitudinal Studies
Protein Isoforms
Homeostasis
Survival Rate
Exercise
Mutation
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Domenighetti, A. A., Chu, P. H., Wu, T., Sheikh, F., Gokhin, D. S., Guo, L. T., ... Chen, J. (2014). Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice. Human Molecular Genetics, 23(1), 209-225. [ddt412]. https://doi.org/10.1093/hmg/ddt412

Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice. / Domenighetti, Andrea A.; Chu, Pao Hsien; Wu, Tongbin; Sheikh, Farah; Gokhin, David S.; Guo, Ling T.; Cui, Ziyou; Peter, Angela K.; Christodoulou, Danos C.; Parfenov, Michael G.; Gorham, Joshua M.; Li, Daniel Y.; Banerjee, Indroneal; Lai, Xianyin; Witzmann, Frank; Seidman, Christine E.; Seidman, Jonathan G.; Gomes, Aldrin V.; Shelton, G. Diane; Lieber, Richard L.; Chen, Ju.

In: Human Molecular Genetics, Vol. 23, No. 1, ddt412, 01.2014, p. 209-225.

Research output: Contribution to journalArticle

Domenighetti, AA, Chu, PH, Wu, T, Sheikh, F, Gokhin, DS, Guo, LT, Cui, Z, Peter, AK, Christodoulou, DC, Parfenov, MG, Gorham, JM, Li, DY, Banerjee, I, Lai, X, Witzmann, F, Seidman, CE, Seidman, JG, Gomes, AV, Shelton, GD, Lieber, RL & Chen, J 2014, 'Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice', Human Molecular Genetics, vol. 23, no. 1, ddt412, pp. 209-225. https://doi.org/10.1093/hmg/ddt412
Domenighetti, Andrea A. ; Chu, Pao Hsien ; Wu, Tongbin ; Sheikh, Farah ; Gokhin, David S. ; Guo, Ling T. ; Cui, Ziyou ; Peter, Angela K. ; Christodoulou, Danos C. ; Parfenov, Michael G. ; Gorham, Joshua M. ; Li, Daniel Y. ; Banerjee, Indroneal ; Lai, Xianyin ; Witzmann, Frank ; Seidman, Christine E. ; Seidman, Jonathan G. ; Gomes, Aldrin V. ; Shelton, G. Diane ; Lieber, Richard L. ; Chen, Ju. / Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 1. pp. 209-225.
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abstract = "Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in fourand- a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing bodymyopathy and Emery-Dreifuss muscular dystrophy. However, itremains tobe clarifiedwhethermutationsinFHL1 cause skeletalmuscleremodelingowingto gain- or loss of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss-offunction effects on skeletalmuscle homeostasis. Histological and functional analyses of soleus, tibialis anterior andsternohyoideusmusclesdemonstratedthatFHL1-nullmicedevelopanage-dependentmyopathyassociated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates inFHL1-nullmice,associatedwithage-dependentimpairmentofmusclecontractile functionanda significantly lower exercise capacity.Analysis of primarymyoblasts isolated fromFHL1-nullmusclesdemonstrated early muscle fiber differentiation and maturation defects,which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations.",
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AU - Sheikh, Farah

AU - Gokhin, David S.

AU - Guo, Ling T.

AU - Cui, Ziyou

AU - Peter, Angela K.

AU - Christodoulou, Danos C.

AU - Parfenov, Michael G.

AU - Gorham, Joshua M.

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AU - Banerjee, Indroneal

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AU - Witzmann, Frank

AU - Seidman, Christine E.

AU - Seidman, Jonathan G.

AU - Gomes, Aldrin V.

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