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Novel depside dimeric compounds for skeletal muscle modulation, methods and uses thereof

A compound, the technology of depsidic acid, applied in the field of novel depsidic acid dimerization compounds, can solve the problem of low regeneration potential of myoblasts

Inactive Publication Date: 2021-10-29
SOC DES PROD NESTLE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Previous experimental therapies that have included myoblast transplantation have not been entirely successful because the more committed and differentiated myoblasts have a lower regenerative potential compared to muscle stem cells

Method used

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  • Novel depside dimeric compounds for skeletal muscle modulation, methods and uses thereof
  • Novel depside dimeric compounds for skeletal muscle modulation, methods and uses thereof
  • Novel depside dimeric compounds for skeletal muscle modulation, methods and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0247] Example 1: Selection of compounds that modulate muscle stem cells

[0248] Selection of human skeletal muscle myoblasts

[0249] The inventors developed a high content screen to test compounds on primary human adult muscle cells in vitro. Human skeletal muscle myoblasts (HSMM) were purchased from Lonza ( https: / / bioscience.lonza.com ). These cells were isolated from normal donor upper arm or leg muscle tissue and used after a second passage. Several donors were tested to ensure cell viability and purity before selecting the final donors who were a 36-year-old Caucasian female (Donor 8) and a 20-year-old Caucasian female (Donor 4).

[0250] Muscle Stem Cell Commitment Assay

[0251] The primary screening assay was based on the detection of high levels of two important myogenic regulators (Pax7 and MyoD) by immunofluorescence. Pax7 and MyoD are major markers of stemness and commitment of muscle stem cells and can be used to monitor muscle stem ce...

Embodiment 2

[0254] Example 2: Myoblast Differentiation Assay

[0255] Human primary myoblasts from two different donors (Donor 8 and Donor 4) were seeded at a density of 3'000 cells per well in 384-well plates in Skeletal Muscle Growth Medium (SKM-M , AMSbio). One day later, differentiation was induced by medium exchange. For treatment, compounds were added directly to myoblast cultures for 96 hours. Myotubes were stained with an antibody against Troponin T to determine Troponin T expression and counterstained with Hoechst 33342 to visualize nuclei. Image acquisition was performed using the ImageXpress (Molecular Devices) platform. Quantification was performed using a custom module analysis based on MetaXpress software for multiwavelength cytoscoring. For each condition, the number of cells was counted to control for compound toxicity, and myotubes were characterized by several readouts in order to assess the level of differentiation and their morphology.

[0256] image 3 - Saf...

Embodiment 4

[0258] Example 4: Diffractive lichenic acid can promote muscle regeneration process in vivo

[0259] To recapitulate the physiological process of muscle regeneration in adult skeletal muscle in response to injury or disease, we injected cardiotoxin intramuscularly into mouse hindlimb muscles. One week before induction of muscle damage, diffracted lichenic acid (100 mg / kg body weight) was administered to mice by oral gavage relative to the water control group. Mice were handled once a day until the end of the experiment. To assess the efficiency of muscle regeneration, previously injured muscles were harvested 5 days after injury and cryosections were prepared. Several myogenic markers are then measured. Cryosections were stained with specific antibodies against Pax7, myogenin, laminin, and embryonic myosin heavy chain (eMHC) expression and counterstained with Hoechst33342 to visualize nuclei. Diffractive lichenic acid is able to promote the process of muscle regeneration ...

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Abstract

The present invention relates to novel depside dimeric compounds for improving skeletal muscle plasticity regeneration to maintain or increase muscle function and / or muscle mass by modulating muscle stem cells. For example, the present invention is useful for subjects to promote muscle repair and / or subjects suffering from precachexia, cachexia, sarcopenia, myopathy, dystrophy and / or recovery after muscle injury or surgery.

Description

technical field [0001] The present invention relates to novel depsipolic acid dimer compounds for improving skeletal muscle plasticity by regulating muscle stem cells to maintain or increase muscle function and / or muscle mass. For example, the present invention may be used in individuals who want to promote muscle repair and / or in individuals suffering from precachexia, cachexia, sarcopenia, myopathy, malnutrition, and / or recovery after muscle injury or surgery. Background technique [0002] Skeletal muscle regeneration is an important mechanism for repairing and maintaining muscle mass and function throughout the lifespan. Skeletal muscle regeneration primarily requires the involvement of myogenic progenitor cells, called muscle stem cells or satellite cells. [0003] Nonproliferative quiescent satellite cells adjacent to resting skeletal muscle can be identified by their variable location between the sarcolemma and basal lamina, high nuclear to cytoplasmic volume ratio, f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00
CPCA61K45/06A61P21/00A61K31/235A61K31/455A61K31/714A61K31/593A61K31/202A61K31/352C07C69/92A23L33/10A61K2300/00
Inventor D·M·巴伦B·布里农J·费奇S·卡拉兹J·米肖Y·拉蒂诺P·斯图尔萨茨
Owner SOC DES PROD NESTLE SA
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