Growth and Muscle Defects in Mice Lacking Adult Myosin Heavy Chain Genes

Acakpo-Satchivi, Leslie; Edelmann, Winfried; Sartorius, Carol A.; Lu, Brian; Wahr, Philip A.; Watkins, Simon C.; Metzger, Joseph M.; Leinwand, Leslie A.; Kucherlapati, Raju

doi:10.1083/jcb.139.5.1219

Cited by 89 publications

(94 citation statements)

References 36 publications

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“…Since MyHC is a major determinant of the maximum unloaded shortening velocity of skeletal muscle contraction, the type of MyHC comprising a sarcomere is of functional significance (2,3,24,26,29,36). Consistent with the latter concept, a functional analysis of skeletal muscle from either MyHC IIb or MyHC IIx/d null mice revealed altered contractile properties that were unique to each null mutation (1,25).…”

mentioning

confidence: 52%

Purα and Purβ Collaborate with Sp3 To Negatively Regulate β-Myosin Heavy Chain Gene Expression duringSkeletal Muscle Inactivity

Ji¹,

Tsika²,

Rindt³

et al. 2007

Molecular and Cellular Biology

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Adult skeletal muscle retains the capability of transcriptional reprogramming. This attribute is readily observable in the non-weight-bearing (NWB) soleus muscle, which undergoes a slow-to-fast fiber type transition concurrent with decreased ␤-myosin heavy chain (␤MyHC) gene expression. Our previous work showed that Sp3 contributes to decreased ␤MyHC gene expression under NWB conditions. In this study, we demonstrate that physical and functional interactions between Sp3, Pur␣, and Pur␤ proteins mediate repression of ␤MyHC expression under NWB conditions. Binding of Pur␣ or Pur␤ to the single-stranded ␤MyHC distal negative regulatory element-sense strand (d␤NRE-S) element is markedly increased under NWB conditions. Ectopic expression of Pur␣ and Pur␤ decreased ␤MyHC reporter gene expression, while mutation of the d␤NRE-S element increased expression in C2C12 myotubes. The d␤NRE-S element conferred Pur-dependent decreased expression on a minimal thymidine kinase promoter. Short interfering RNA sequences specific for Sp3 or for Pur␣ and Pur␤ decreased endogenous Sp3 and Pur protein levels and increased ␤MyHC reporter gene expression in C2C12 myotubes. Immunoprecipitation assays revealed an association between endogenous Pur␣, Pur␤, and Sp3, while chromatin immunoprecipitation assays demonstrated Pur␣, Pur␤, and Sp3 binding to the ␤MyHC proximal promoter region harboring the d␤NRE-S and C-rich elements in vivo. These data demonstrate that Pur proteins collaborate with Sp3 to regulate a transcriptional program that enables muscle cells to remodel their phenotype.

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mentioning

confidence: 52%

Purα and Purβ Collaborate with Sp3 To Negatively Regulate β-Myosin Heavy Chain Gene Expression duringSkeletal Muscle Inactivity

Ji¹,

Tsika²,

Rindt³

et al. 2007

Molecular and Cellular Biology

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“…18 Inactivation of the genes encoding adult fast skeletal myosin heavy chain IIb and IId/x and creation of MyHC IIx and MyHC IIb null mice have indicated that these genes are required for the normal muscle development and function of adult skeletal muscle in the mouse. [28][29][30][31][32] MyHC IId/x null mutants showed growth inhibition, muscle weakness and histological abnormalities with abnormal muscle fibers and increased interstitial connective tissue. 31 There was a compensatory increase in MyHC IIa expression in the MyHC IId/x null mice.…”

Section: Discussionmentioning

confidence: 99%

Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations

et al. 2013

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Myosin myopathies comprise a group of inherited diseases caused by mutations in myosin heavy chain (MyHC) genes. Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers. In this study, we describe for the first time the clinical and morphological characteristics of recessive myosin IIa myopathy associated with MYH2 missense mutations. Seven patients of five different families with a myopathy characterized by ophthalmoplegia and mild-to-moderate muscle weakness were investigated. Muscle biopsy was performed to study morphological changes and MyHC isoform expression. Five of the patients were homozygous for MYH2 missense mutations, one patient was compound heterozygous for a missense and a nonsense mutation and one patient was homozygous for a frame-shift MYH2 mutation. Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein. We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.

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“…There is accordingly reason to believe that this group of myopathies may have been misdiagnosed and lumped together with other neuromuscular disorders. Experimental animal studies have shown distinct patterns of muscle dysfunction in IIx and IIb MyHC null mice, while heterozygous mice are clinically normal (6). Missense mutation in the β/slow MyHC gene causes a familial hypertrophic cardiomyopathy-like disease in heterozygous mice, indicating that missense mutations are more deleterious than nulls (7).…”

Section: Introductionmentioning

confidence: 99%

Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)

Lionikas

et al. 2006

Neuromuscular Disorders

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The pathogenic events leading to the progressive muscle weakness in patients with a E706K mutation in the head of the myosin heavy chain (MyHC) IIa were analysed at the muscle cell and motor protein levels. Contractile properties were measured in single muscle fiber segments using the skinned fiber preparation and a single muscle fiber in vitro motility assay. A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. At the single muscle fiber level, on the other hand, a general decrease was observed in the number of preparations where the specific criteria for acceptance were fulfilled irrespective of MyHC isoform expression. Our results provide evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle cells irrespective of MyHC isoform expression.

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Growth and Muscle Defects in Mice Lacking Adult Myosin Heavy Chain Genes

Cited by 89 publications

References 36 publications

Purα and Purβ Collaborate with Sp3 To Negatively Regulate β-Myosin Heavy Chain Gene Expression duringSkeletal Muscle Inactivity

Purα and Purβ Collaborate with Sp3 To Negatively Regulate β-Myosin Heavy Chain Gene Expression duringSkeletal Muscle Inactivity

Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations

Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)

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