Skeletal Muscle Involvement in Friedreich Ataxia

Abstract

Friedreich Ataxia (FRDA) is an inherited neuromuscular disorder triggered by a deficit of the mitochondrial protein frataxin. At a cellular level, frataxin deficiency results in insufficient iron-sulfur cluster biosynthesis and impaired mitochondrial function and adenosine triphosphate production. The main clinical manifestation is a progressive balance and coordination disorder which depends on the involvement of peripheral and central sensory pathways as well as of the cerebellum. Besides the neurological involvement, FRDA affects also the striated muscles. The most prominent manifestation is a hypertrophic cardiomyopathy, which also represents the major determinant of premature mortality. Moreover, FRDA displays skeletal muscle involvement, which contributes to the weakness and marked fatigue evident throughout the course of the disease. Herein, we review skeletal muscle findings in FRDA generated by functional imaging, histology, as well as multiomics techniques in both disease models and in patients. Altogether, these findings corroborate a disease phenotype in skeletal muscle and support the notion of progressive mitochondrial damage as a driver of disease progression in FRDA. Furthermore, we highlight the relevance of skeletal muscle investigations in the development of biomarkers for early-phase trials and future therapeutic strategies in FRDA.

Keywords: Friedreich Ataxia; biomarker; frataxin; mitochondria; proteomics; skeletal muscle; transcriptomics.

Figure 1

Interactome of differentially expressed proteins in skeletal muscle of FRDA adapted from the STRING database (reference: Indelicato et al. 2023b, [34]). MICOS: mitochondrial contact site and cristae organizing system.

Figure 2

Mitochondrial localization of top downregulated proteins in skeletal muscle in FRDA (reference: Indelicato et al. 2023b, [34]). MICOS: mitochondrial contact site and cristae organizing system. Figure created with BioRender.com.