A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy

Liu, Jian; Campagna, Jesus; John, Varghese; Damoiseaux, Robert; Mokhonova, Ekaterina; Becerra, Diana; Meng, Huan; McNally, Elizabeth M.; Kramerova, Irina; Spencer, Melissa J.

doi:10.1016/j.xcrm.2020.100122

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…Interestingly, it has been recently shown that calcium dyshomeostasis may be an early phenomenon in this model ( DiFranco et al, 2016 ). In contrast to reports from C3KO mice beyond 4 months old ( Ermolova et al, 2011 ; Kramerova et al, 2016 ; Liu et al, 2020 ), we found that 2-month-old C3KO mice show similar performance in grip strength and resistance to fatigue tests compared to controls, suggesting that at this age C3KO are presymptomatic. Additionally, hyper-CKemia has been previously described in the early stages of the disease ( Urtasun et al, 1998 ; Fanin and Angelini 2015 ).…”

Section: Discussioncontrasting

confidence: 99%

Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations

Lasa-Elgarresta

Mosqueira-Martín

González-Imaz

et al. 2022

Front. Cell Dev. Biol.

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LGMDR1 is caused by mutations in the CAPN3 gene that encodes calpain 3 (CAPN3), a non-lysosomal cysteine protease necessary for proper muscle function. Our previous findings show that CAPN3 deficiency leads to reduced SERCA levels through increased protein degradation. This work investigates the potential contribution of the ubiquitin-proteasome pathway to increased SERCA degradation in LGMDR1. Consistent with our previous results, we observed that CAPN3-deficient human myotubes exhibit reduced SERCA protein levels and high cytosolic calcium concentration. Treatment with the proteasome inhibitor bortezomib (Velcade) increased SERCA2 protein levels and normalized intracellular calcium levels in CAPN3-deficient myotubes. Moreover, bortezomib was able to recover mutated CAPN3 protein in a patient carrying R289W and R546L missense mutations. We found that CAPN3 knockout mice (C3KO) presented SERCA deficits in skeletal muscle in the early stages of the disease, prior to the manifestation of muscle deficits. However, treatment with bortezomib (0.8 mg/kg every 72 h) for 3 weeks did not rescue SERCA levels. No change in muscle proteasome activity was observed in bortezomib-treated animals, suggesting that higher bortezomib doses are needed to rescue SERCA levels in this model. Overall, our results lay the foundation for exploring inhibition of the ubiquitin-proteasome as a new therapeutic target to treat LGMDR1 patients. Moreover, patients carrying missense mutations in CAPN3 and presumably other genes may benefit from proteasome inhibition by rescuing mutant protein levels. Further studies in suitable models will be necessary to demonstrate the therapeutic efficacy of proteasome inhibition for different missense mutations.

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Section: Discussioncontrasting

confidence: 99%

Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations

Lasa-Elgarresta

Mosqueira-Martín

González-Imaz

et al. 2022

Front. Cell Dev. Biol.

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“…The functional significance of these differentially expressed muscle genes were summarized in Table 6 . Decreased muscle expression of Csrp3, Fhl1, Myl2 and Tnnc1 and increased expression of Itpr1stimulate muscle regeneration and improve muscle function [ 26 , 27 , 30 , 31 , 32 , 33 , 34 , 38 ]. Decreased expression of Cyfip2 improves remodeling of extracellular matrix and leads to accelerated muscle regeneration [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia

Mak

Querfeld

Gonzalez

et al. 2021

Cells

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Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 μg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)2D3 in CKD mice. Repletion of 25(OH)D3 in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.

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“…CAPN3 knockout studies have indicated that Ca 2+ /calmodulin-dependent protein kinase II (Ca-CaMKII)-mediated signal transduction is impaired ( 81 ), which not only decreases the slow muscle fiber phenotype and the fast muscle fiber phenotype ( 82 , 83 ), but also lowers the level of p38 MAPK activation. Eventually, the level of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α; a transcriptional co-regulator that coordinates muscle adaptive response) is decreased, leading to the decreased levels of transcription of genes involved in muscle adaptation ( 40 ).…”

Section: Capn3 In Diseasesmentioning

confidence: 99%

CAPN3: A muscle‑specific calpain with an important role in the pathogenesis of diseases (Review)

Chen

Tang

et al. 2021

Int J Mol Med

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Calpains are a family of Ca 2+ -dependent cysteine proteases that participate in various cellular processes. Calpain 3 (CAPN3) is a classical calpain with unique N-terminus and insertion sequence 1 and 2 domains that confer characteristics such as rapid autolysis, Ca 2+ -independent activation and Na + activation of the protease. CAPN3 is the only muscle-specific calpain that has important roles in the promotion of calcium release from skeletal muscle fibers, calcium uptake of sarcoplasmic reticulum, muscle formation and muscle remodeling. Studies have indicated that recessive mutations in CAPN3 cause limb-girdle muscular dystrophy (MD) type 2A and other types of MD; eosinophilic myositis, melanoma and epilepsy are also closely related to CAPN3. In the present review, the characteristics of CAPN3, its biological functions and roles in the pathogenesis of a number of disorders are discussed.

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A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy

Cited by 5 publications

References 47 publications

Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations

Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations

Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia

CAPN3: A muscle‑specific calpain with an important role in the pathogenesis of diseases (Review)

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