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Spinal Muscle Degeneration in Dysferlinopathy Affects Gait and Identifies Cellular and Therapeutic Target

ABSTRACT: Unlike axial myopathy, which is primarily associated with weakness in the spinal muscles, Limb Girdle Muscular Dystrophy 2B/R2 (LGMD2B/R2; dysferlinopathy) causes loss of limb as well as pelvic and shoulder girdle muscles. However, spinal pathology is often reported in dysferlinopathy patients. Through a cross-sectional magnetic resonance imaging (MRI) analysis of patients with dysferlinopathy and longitudinal analysis of dysferlinopathic mouse model we uncover early-onset and progressive adipogenic degeneration of spinal muscles as a hallmark of this disease. This is caused by region-specific spinal muscle degeneration, with the iliocostalis, longissimus, and spinalis muscles being most affected. Notably, longitudinal analysis of mouse showed over five-fold greater adipogenic loss of spinal muscle compared to the limb muscles with spinal muscle degeneration preceded the limb muscles. Spinal muscle loss in mice causes decreased spinal tone causing flattening of the body along its length and onset of gait abnormalities. At cellular level, spinal muscle degeneration follows accumulation of damaged myofibers in the affected muscles, and to subsequent increase in local inflammation and accumulation of fibroadipogenic precursors (FAPs). FAPs isolated from spinal muscles display high levels of spontaneous adipogenesis ex vivo, which is greater than FAPs from limb muscles. To target adipogenic differentiation of spinal FAPs, we performed in vitro drug testing and identified a GSK3 inhibitor and an FDA-approved HDAC inhibitor as potential therapeutics. These findings reveal a poorly recognized anatomical feature of dysferlinopathy, elucidate its cellular mechanisms, and identify potential therapeutic strategies to address spinal muscle degeneration in dysferlinopathy.

ORGANISM(S): Mus musculus

PROVIDER: GSE333908 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration - is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an "HDAC-myomiR-BAF60 variant network" regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) miR-1.2, miR-133 and miR-206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. miRNA modulation upon Histone Deacetylase inhibition in Fibro-Adipogenic Progenitors (FAPs) derived from young mdx mice was evaluated by small RNA-sequencing in 2 controls and 2 treated samples

Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration M-bM-^@M-^S is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an M-bM-^@M-^\HDAC-myomiR-BAF60 variant networkM-bM-^@M-^] regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a M-bM-^@M-^\latentM-bM-^@M-^] myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) 1.2, 133 and 206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. Genome-wide chromatin accessibility patterns in FAPs cells derived from mdx mice at different ages treated either with HDAC inhibitor Trichostatin A (TSA) or with vehicle (saline solution) were assessed using NA-seq (PMID: 19289091)

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Spinal Muscle Degeneration in Dysferlinopathy Affects Gait and Identifies Cellular and Therapeutic Target

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