Non-myogenic mesenchymal cells contribute to muscle degeneration in facioscapulohumeral muscular dystrophy patients

Abstract

Muscle-resident non-myogenic mesenchymal cells play key roles that drive successful tissue regeneration within the skeletal muscle stem cell niche. These cells have recently emerged as remarkable therapeutic targets for neuromuscular disorders, although to date they have been poorly investigated in facioscapulohumeral muscular dystrophy (FSHD). In this study, we characterised the non-myogenic mesenchymal stromal cell population in FSHD patients’ muscles with signs of disease activity, identified by muscle magnetic resonance imaging (MRI), and compared them with those obtained from apparently normal muscles of FSHD patients and from muscles of healthy, age-matched controls. Our results showed that patient-derived cells displayed a distinctive expression pattern of mesenchymal markers, along with an impaired capacity to differentiate towards mature adipocytes in vitro, compared with control cells. We also demonstrated a significant expansion of non-myogenic mesenchymal cells (identified as CD201- or PDGFRA-expressing cells) in FSHD muscles with signs of disease activity, which correlated with the extent of intramuscular fibrosis. In addition, the accumulation of non-myogenic mesenchymal cells was higher in FSHD muscles that deteriorate more rapidly. Our results prompt a direct association between an accumulation, as well as an altered differentiation, of non-myogenic mesenchymal cells with muscle degeneration in FSHD patients. Elucidating the mechanisms and cellular interactions that are altered in the affected muscles of FSHD patients could be instrumental to clarify disease pathogenesis and identifying reliable novel therapeutic targets.

The DUX4–HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected

“…This indicates that the DUX4–HIF1α axis is not as simple as expected and that targeting HIF1α might be challenging in the context of FSHD therapeutic approaches. Finally, given (I) the regeneration defects in FSHD [ 89 , 90 , 91 ], (II) the role of HIF1α in this process [ 38 , 40 ] and (III) the impact of DUX4 expression on the HIF1α pathway depending on the differentiation state, further investigations, especially in cellular actors of muscle regeneration (e.g., satellite cells) appear critical for a better understanding of FSHD-associated muscle regeneration disturbances. Moreover, regarding the pivotal role of HIF1α in muscle metabolism, it will be important to clarify whether metabolic disturbances could contribute to the development of muscle dysfunction in FSHD.…”

FSHD muscle shows perturbation in fibroadipogenic progenitor cells, mitochondrial function and alternative splicing independently of inflammation

“…FAPs are activated and proliferate after muscle injury and differentiate following specific molecular cues into specialized cells that prepare the extra-cellular matrix to support muscle regeneration. Mis-regulation of FAP function has been implicated in aberrant muscle regeneration in several neuromuscular disorders including LGMD2B [ 85 ], ALS [ 86 ] and recently FSHD [ 53 , 55 , 58 ]. FAP dysregulation in FSHD was first noted in a mouse model of stochastic transient DUX4 expression, which resulted in an increased FAP gene expression signature [ 58 ] that was validated histologically and found to associate with muscle fibrosis post injury [ 87 ].…”

“…Myogenic cells are not the only perturbed cell type in FSHD, implicating non-myogenic cell types resident in muscle, particularly fibroadipogenic progenitor (FAP) cells [ 53 , 58 ]. FAPs comprise a heterogenous mesenchymal cell population, which interact with immune cells and muscle stem cells to facilitate muscle regeneration.…”

“…Mis-regulation of FAPs contributes to fibrosis and fat infiltration in other forms of muscular dystrophy [ 59 ]. Recent work indicates a similar mis-regulation of FAPs may exist in FSHD [ 53 , 58 ]. Peripheral blood mononuclear cells (PBMCs) from FSHD patients have been examined to develop minimally invasive blood-based biomarkers of disease progression.…”

The DUX4-HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected

“…This indicated that the DUX4-HIF1α axis was not as simple as expected and that targeting HIF1α might be challenging in the context of FSHD therapeutic approaches. Finally, given (I) the regeneration defects in FSHD [79,80], (II) the role of HIF1α in this process [41], (III) the impact of DUX4 expression on the HIF1α pathway depending on the differentiation state, further investigations, especially in satellite cells, appear critical for a better understanding of FSHD-associated muscle regeneration disturbances. Moreover, regarding the pivotal role of HIF1α in muscle metabolism, it will be important to clarify whether metabolic disturbances could contribute to the development of muscle dysfunction in FSHD.…”