P5: Muscle metabolism

Subproject Speakers
Berlin: Michael Boschmann, MD
Paris:  Pierre Carlier, PhD

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy and is characterized by onset of weakness in an initially restricted and characteristic distribution, beginning with facial weakness, followed sequentially by scapular fixator, humeral, truncal, and lower-extremity muscle weakness, wasting and fatigueability. Its underlying molecular pathophysiology is not well understood, which complicates the development of therapeutic strategies. FSHD is an autosomal-dominant inherited condition and is caused by a deletion of a repetitive element on chromosome 4q35 known as D4Z4. This region contains a transcriptional silencer. Deletion of D4Z4 leads to overly active genes including FSHD-related gene (FRG1). FRG1 transgenic mice indeed develop the FSHD phenotype. FRG1 is located 120 kb from the D4Z4 repeats and encodes an evolutionarily highly conserved nuclear protein that may play a role in RNA biogenesis. A very recent report revealed that FRG1 is crucial for angiogenesis, linking FRG1 to FSHD-associated vasculopathy.3 FSHD has also been associated with dysfunction of adenine nucleotide translocase (ANT1), a product of a gene that is also located on 4q, and which is possibly de-repressed. These data suggest that FSHD might also affect mitochondrial function, although this question was not yet investigated. Most interestingly, impaired differentiation of myoblasts has been described in affected muscles of FSHD patients and a genome-wide mRNA-scan suggested that the insulin receptor pathway, which is known to modify the differentiation process of myoblasts, may be dysregulated in FSHD. As a result of a recent pilot study, we found insulin resistance in four FSHD patients. In summary, there is evidence that metabolic defects are associated with FSHD; however, the relevance and functional importance of those findings is entirely unclear. Despite the apparent impact of metabolism and specifically the insulin-signaling cascade in the differentiation and regeneration of muscle, this issue has not yet been investigated in FSHD or in other muscular dystrophies.


Teresa Gerhalter, doctoral student

Master, Technology
Graz University of Technology, Austria

Working title
Characterization of the dystrophic muscle by 23Na NMR and 1H NMR T2 spectrum

Anna Pakula,  MyoGrad doctoral student 2010-2015

Completed doctoral project:
Muscle metabolism and cyclin A1 in facioscapulohumeral muscular dystrophy-1 (FSHD-1)

Date and place of thesis defense:
September 22, 2015 in Berlin
Doctoral degree from FU Berlin

Matthew Thorley, MyoGrad doctoral student 2013-2016

Completed doctoral project:
The analysis of the dystrophin interactome

Date and place of thesis defense:
December 7, 2016 in Paris
Joint doctoral degree from UPMC, Paris VI and from FU Berlin