Thyroid-stimulating hormone receptor signaling restores skeletal muscle stem cell regeneration in rats with muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe and progressive myopathy leading to motor and cardiorespiratory impairment. We analyzed samples from patients with DMD and a preclinical rat model of severe DMD and determined that compromised repair capacity of muscle stem cells in DMD is associated with early and progressive muscle stem cell senescence. We also found that extraocular muscles (EOMs), which are spared by the disease in patients, contain muscle stem cells with long-lasting regenerative potential. Using single-cell transcriptomics analysis of muscles from a rat model of DMD, we identified the gene encoding thyroid-stimulating hormone receptor ( Tshr ) as highly expressed in EOM stem cells. Further, TSHR activity was involved in preventing senescence. Forskolin, which activates signaling downstream of TSHR, was found to reduce senescence of skeletal muscle stem cells, increase stem cell regenerative potential, and promote myogenesis, thereby improving muscle function in DMD rats. These findings indicate that stimulation of adenylyl cyclase leads to muscle repair in DMD, potentially providing a therapeutic approach for patients with the disease.

Spatial Transcriptomic and Metabolomic Landscapes of Oral Submucous Fibrosis‐Derived Oral Squamous Cell Carcinoma and its Tumor Microenvironment

“…The results showed that clusters constitution (Figure 1E ) and transcriptomic patterns (Figure 1F ) were consistent with the pathological features of each tissue region, such as epithelial cell marker KRT17 in the Tumor region, [ 28 ] differentiation‐related gene CALML5 in the Adjacent Epithelium or ISC region, [ 29 ] immune‐related gene IGHG2 in the OSF region, [ 30 ] lipid metabolism‐related apolipoprotein APOE in the Stroma region, [ 31 , 32 ] and myocyte signature DES in the Muscle region (Figure 1F ). [ 33 ]…”

Receptor interacting protein kinase‐3 mediates both myopathy and cardiomyopathy in preclinical animal models of Duchenne muscular dystrophy

“…This model is marked by continuous and active cycles of myonecrosis/regeneration in the first 6 months of the disease's progression, which are eventually halted by the animals' depleted repair capacity towards the end of their lifespan. 31 …”

Regulation of Satellite Cells Functions during Skeletal Muscle Regeneration: A Critical Step in Physiological and Pathological Conditions

“…Along this line, the depletion of senescent cells by senolytic drugs improves muscle regeneration in dystrophic mice by decreasing the expression of IL-6, TGF-β, and IL-1β [ 144 , 145 ]. Furthermore, preventing senescence increases the regenerative potential of SCs and improves muscle functions [ 146 ]. In addition to senescence, altered plasticity of SCs has also been demonstrated over the years.…”