Drs. Regula Furrer and Christoph Handschin of the University of Basel have a new publication in Life Sci Alliance entitled “Metabolic dysregulation contributes to the development of dysferlinopathy.”

This paper describes Furrer and Handschin’s work on a Jain Foundation-funded project that was intended to explore the therapeutic potential of increasing PGC-1α expression in dysferlinopathy. The findings are surprising and reveal an unexpected role for dysferlin in muscle cell energy metabolism.

PGC-1α is a key transcriptional coactivator known to play a crucial role in maintaining energy homeostasis. Several studies have shown that the activation of PGC-1α is protective in various contexts of impaired muscle function, including in animal models of DMD. In contrast to similar studies in mdx mice, the overexpression of PGC-1α accelerated the disease progression in dysferlin-deficient mice.

A closer analysis of this result uncovered that dysferlin null muscles exhibit increased glucose uptake and lower abundance of proteins involved in glycolysis and glycogen breakdown, leading to excess glycogen accumulation. Moreover, dysferlin-deficient muscles showed mitochondrial abnormalities, increased expression of proteins involved in death signaling, and substantial changes to the muscle proteome.

The Handschin lab attempted to reduce glycogen accumulation with exercise, which led to improvements in muscle mass and balance beam performance. However, the team observed reduced myofiber integrity as measured by Evan’s blue dye uptake. The authors note that this damage could be due to the repeated bouts of exercise.

The revelation of a metabolic defect in dysferlin-deficient muscle as well as the demonstration that increasing PGC-1α expression exacerbates the muscle pathology in dysferlinopathy provide new insights into understanding the effects of dysferlin deficiency and further separates it from the pathophysiology of dystrophin deficiency.

We encourage our readers to check out the full data and discussion of these findings here: https://pmc.ncbi.nlm.nih.gov/articles/PMC11871293/

Image source: Furrer R, Dilbaz S, Steurer SA, Santos G, Karrer-Cardel B, Ritz D, Sinnreich M, Handschin C. Metabolic dysregulation contributes to the development of dysferlinopathy. Life Sci Alliance. 2025 Feb 28;8(5):e202402991. doi: 10.26508/lsa.202402991. PMID: 40021220; PMCID: PMC11871293.