Small-molecule activation of lysosomal TRP channels ameliorates Duchenne muscular dystrophy in mouse models

Abstract

Duchenne muscular dystrophy (DMD) is a devastating disease caused by mutations in dystrophin that compromise sarcolemma integrity. Currently, there is no treatment for DMD. Mutations in transient receptor potential mucolipin 1 (ML1), a lysosomal Ca2+ channel required for lysosomal exocytosis, produce a DMD-like phenotype. Here, we show that transgenic overexpression or pharmacological activation of ML1 in vivo facilitates sarcolemma repair and alleviates the dystrophic phenotypes in both skeletal and cardiac muscles of mdx mice (a mouse model of DMD). Hallmark dystrophic features of DMD, including myofiber necrosis, central nucleation, fibrosis, elevated serum creatine kinase levels, reduced muscle force, impaired motor ability, and dilated cardiomyopathies, were all ameliorated by increasing ML1 activity. ML1-dependent activation of transcription factor EB (TFEB) corrects lysosomal insufficiency to diminish muscle damage. Hence, targeting lysosomal Ca2+ channels may represent a promising approach to treat DMD and related muscle diseases.

Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors

“…Loss or mutation of TRPML1 causes the neurodegenerative lysosomal storage disorder mucolipidosis type IV 1 ; vice versa activation of TRPML1 clears intraneuronal Aβ in preclinical models of HIV infection 2 and protects human dopaminergic neurons from α-synuclein toxicity through increased lysosomal exocytosis 3 . TRPML1 is also essential for sarcolemma repair to prevent muscular dystrophy 4 , and small molecule activation of TRPML1 ameliorates Duchenne muscular dystrophy 5 . TRPML1 further plays a role in gastric acid secretion and may represent a therapeutic target for chronic Helicobacter pylori infection 6 – 8 .…”

“…In recent years several TRPML channel activators have been developed by different groups, e.g. SF-22, MK6-83, ML-SA1, or ML-SA5 5 , 19 – 21 . In addition, TRPML isoform-selective agonists have been discovered recently such as a TRPML2-selective agonist, ML2-SA1 22 or TRPML3-selective agonists, SN-2 and EVP-21 20 , 22 .…”

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

“…In mice, genetic ablation of TRPML1 resulted in DMD-like phenotype with an impairment in the membrane sealing in skeletal muscles (Cheng et al, 2014). On the other hand, transgenic overexpression or pharmacological activation of TRPML1 in vivo facilitates sarcolemma repair and alleviates dystrophic phenotypes in both skeletal and cardiac muscles of mdx mice (Yu et al, 2020). These studies further show that TRPML1 activation increased lysosomal biogenesis by activating the transcription factor EB and thereby facilitated sarcolemma repair to reduce muscle damage in mdx mice (Yu et al, 2020).…”

“…On the other hand, transgenic overexpression or pharmacological activation of TRPML1 in vivo facilitates sarcolemma repair and alleviates dystrophic phenotypes in both skeletal and cardiac muscles of mdx mice (Yu et al, 2020). These studies further show that TRPML1 activation increased lysosomal biogenesis by activating the transcription factor EB and thereby facilitated sarcolemma repair to reduce muscle damage in mdx mice (Yu et al, 2020). Therefore, targeting lysosomal Ca 2+ channels may represent a promising approach to treat DMD and related muscle diseases.…”

“…This may result in increased activity of Ca 2+ leak channels because an antagonist of these channels reduced the higher levels of hydrolysis in dystrophic myotubes to nearly normal levels (Alderton and Steinhardt, 2000). Recent studies have demonstrated the involvement of transient receptor potential mucolipin 1 (TRPML1), a lysosomal Ca 2+ release channel needed for lysosomal exocytosis in membrane repair in DMD (Cheng et al, 2014;Yu et al, 2020). In mice, genetic ablation of TRPML1 resulted in DMD-like phenotype with an impairment in the membrane sealing in skeletal muscles (Cheng et al, 2014).…”