Growth hormone secretagogues modulate inflammation and fibrosis in mdx mouse model of Duchenne muscular dystrophy

Boccanegra, Brigida; Cappellari, Ornella; Mantuano, Paola; Trisciuzzi, Daniela; Mele, Antonietta; Tulimiero, Lisamaura; Bellis, Michela De; Cirmi, Santa; Sanarica, Francesca; Cerchiara, Alessandro Giovanni; Conte, Elena; Meanti, Ramona; Rizzi, Laura; Bresciani, Elena; Denoyelle, Séverine; Fehrentz, Jean‐Alain; Cruciani, Gabriele; Nicolotti, Orazio; Liantonio, Antonella; Torsello, Antonio; Luca, Annamaria De

doi:10.3389/fimmu.2023.1119888

Cited by 7 publications

(4 citation statements)

References 59 publications

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“…5 A, bottom panel ). This occurred because of the characteristic pseudohypertrophy of mdx muscle, which is thought to be due to increased inflammation and fibrosis stemming from increased muscle degeneration in mdx muscle [ 42 , 43 ]. As a result, the mdx muscle was 40% more massive than control B10 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Exploring lipin1 as a promising therapeutic target for the treatment of Duchenne muscular dystrophy

Jama,

Alshudukhi,

Burke

et al. 2024

J Transl Med

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Background Duchenne muscular dystrophy (DMD) is a progressive and devastating muscle disease, resulting from the absence of dystrophin. This leads to cell membrane instability, susceptibility to contraction-induced muscle damage, subsequent muscle degeneration, and eventually disability and early death of patients. Currently, there is no cure for DMD. Our recent studies identified that lipin1 plays a critical role in maintaining myofiber stability and integrity. However, lipin1 gene expression levels are dramatically reduced in the skeletal muscles of DMD patients and mdx mice. Methods To identify whether increased lipin1 expression could prevent dystrophic pathology, we employed unique muscle-specific mdx:lipin1 transgenic (mdx:lipin1Tg/0) mice in which lipin1 was restored in the dystrophic muscle of mdx mice, intramuscular gene delivery, as well as cell culture system. Results We found that increased lipin1 expression suppressed muscle degeneration and inflammation, reduced fibrosis, strengthened membrane integrity, and resulted in improved muscle contractile and lengthening force, and muscle performance in mdx:lipin1Tg/0 compared to mdx mice. To confirm the role of lipin1 in dystrophic muscle, we then administered AAV1-lipin1 via intramuscular injection in mdx mice. Consistently, lipin1 restoration inhibited myofiber necroptosis and lessened muscle degeneration. Using a cell culture system, we further found that differentiated primary mdx myoblasts had elevated expression levels of necroptotic markers and medium creatine kinase (CK), which could be a result of sarcolemmal damage. Most importantly, increased lipin1 expression levels in differentiated myoblasts from mdx:lipin1Tg/0 mice substantially inhibited the elevation of necroptotic markers and medium CK levels. Conclusions Overall, our data suggest that lipin1 is a promising therapeutic target for the treatment of dystrophic muscles.

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Section: Resultsmentioning

confidence: 99%

Exploring lipin1 as a promising therapeutic target for the treatment of Duchenne muscular dystrophy

Jama,

Alshudukhi,

Burke

et al. 2024

J Transl Med

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“…Gene expression analysis was performed in gastrocnemius (GC) muscles of different experimental groups according to a previous study ( Boccanegra et al, 2023a ). For each muscle sample, total RNA was isolated with TRIzol (Thermo Fisher Scientific, Waltham, United States, cod.10296028).…”

Section: Methodsmentioning

confidence: 99%

Branched-chain amino acids and L-alanine supplementation ameliorate calcium dyshomeostasis in sarcopenia: New insights for nutritional interventions

Conte,

Mantuano,

Boccanegra

et al. 2024

Front. Pharmacol.

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Introduction: During aging, sarcopenia and decline in physiological processes lead to partial loss of muscle strength, atrophy, and increased fatigability. Muscle changes may be related to a reduced intake of essential amino acids playing a role in proteostasis. We have recently shown that branched-chain amino acid (BCAA) supplements improve atrophy and weakness in models of muscle disuse and aging. Considering the key roles that the alteration of Ca2+-related homeostasis and store-operated calcium entry (SOCE) play in several muscle dysfunctions, this study has been aimed at gaining insight into the potential ability of BCAA-based dietary formulations in aged mice on various players of Ca2+ dyshomeostasis.Methods: Seventeen-month-old male C57BL/6J mice received a 12-week supplementation with BCAAs alone or boosted with two equivalents of L-alanine (2-Ala) or with dipeptide L-alanyl-L-alanine (Di-Ala) in drinking water. Outcomes were evaluated on ex vivo skeletal muscles indices vs. adult 3-month-old male C57BL/6J mice.Results: Ca2+ imaging confirmed a decrease in SOCE and an increase of resting Ca2+ concentration in aged vs. adult mice without alteration in the canonical components of SOCE. Aged muscles vs. adult muscles were characterized by a decrease in the expression of ryanodine receptor 1 (RyR1), the Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA) pump, and sarcalumenin together with an alteration of the expression of mitsugumin 29 and mitsugumin 53, two recently recognized players in the SOCE mechanism. BCAAs, particularly the formulation BCAAs+2-Ala, were able to ameliorate all these alterations.Discussion: These results provide evidence that Ca2+ homeostasis dysfunction plays a role in the functional deficit observed in aged muscle and supports the interest of dietary BCAA supplementation in counteracting sarcopenia-related SOCE dysregulation.

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“…Gene expression experiments were performed at the myoblast stage and the various differentiation time points (as discussed above). RNA was extracted with the RNeasy Micro kit (QIAGEN) following the supplier's instructions 32 . Variable amounts of RNA (between 1 and 2 μg) were then reverse transcribed to cDNA with iScript gDNA Clear cDNA Synthesis Kit (172‐5035 Bio‐Rad Laboratories, Inc) following manufacturer instructions.…”

Section: Methodsmentioning

confidence: 99%

“…RNA was extracted with the RNeasy Micro kit (QIAGEN) following the supplier's instructions. 32 Variable amounts of RNA (between 1 and 2 μg) were then reverse transcribed to cDNA with iScript gDNA Clear cDNA Synthesis Kit (172-5035 Bio-Rad Laboratories, Inc) following manufacturer instructions. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed via the CFX384 Connect Real-Time PCR System (Bio-Rad) by using PrimePCR assays SYBR green with custom-made plates.…”

Section: Rna Extraction Reverse Transcription and Gene Expressionmentioning

confidence: 99%

Ion channels as biomarkers of altered myogenesis in myofiber precursors of Duchenne muscular dystrophy

Cerchiara,

Imbrici,

Quarta

et al. 2024

Annals of the New York Academy of Sciences

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Myogenesis is essential for skeletal muscle formation, growth, and regeneration and can be altered in Duchenne muscular dystrophy (DMD), an X‐linked disorder due to the absence of the cytoskeletal protein dystrophin. Ion channels play a pivotal role in muscle differentiation and interact with the dystrophin complex. To investigate ion channel involvement in myogenesis in dystrophic settings, we performed electrophysiological characterization of two immortalized mouse cell lines, wild‐type (WT) H2K‐2B4 and the dystrophic (DYS) H2K‐SF1, and measured gene expression of differentiation markers and ion channels. Inward and outward currents/density increased as differentiation progressed in both WT and DYS cells. However, day‐11 DYS cells showed higher (27%) inward current density with an increased expression ratio of Scn5a/Scn4a and decreased (48%) barium‐sensitive outward current compared to WT. Furthermore, day‐11 DYS cells showed more positive resting membrane potential (+10 mV) and lower membrane capacitance (50%) compared to WT. DYS cells also had reduced Myog and Myf5 expression at days 6 and 11. Overall, ion channel profile and myogenesis appeared altered in DYS cells. These results are a first step in validating ion channels as potential drug targets to ameliorate muscle degeneration in DMD settings and as differentiation biomarkers in innovative platforms.

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Growth hormone secretagogues modulate inflammation and fibrosis in mdx mouse model of Duchenne muscular dystrophy

Cited by 7 publications

References 59 publications

Exploring lipin1 as a promising therapeutic target for the treatment of Duchenne muscular dystrophy

Exploring lipin1 as a promising therapeutic target for the treatment of Duchenne muscular dystrophy

Branched-chain amino acids and L-alanine supplementation ameliorate calcium dyshomeostasis in sarcopenia: New insights for nutritional interventions

Ion channels as biomarkers of altered myogenesis in myofiber precursors of Duchenne muscular dystrophy

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