Chronic Systemic Curcumin Administration Antagonizes Murine Sarcopenia and Presarcopenia.

Curcumin administration attenuates muscle disuse atrophy, but its effectiveness against aging-induced, selective loss of mass or force (presarcopenia or asthenia/dynopenia), or combined loss (sarcopenia), remains controversial. A new systemic curcumin treatment was developed and tested in 18-month-old C57BL6J and C57BL10ScSn male mice. The effects on survival, liver toxicity, loss of muscle mass and force, and satellite cell responsivity and commitment were evaluated after 6-month treatment. Although only 24-month-old C57BL10ScSn mice displayed age-related muscle impairment, curcumin significantly increased survival of both strains (+20-35%), without signs of liver toxicity. Treatment prevented sarcopenia in soleus and presarcopenia in EDL of C57BL10ScSn mice, whereas it did not affect healthy-aged muscles of C57BL6J. Curcumin-treated old C57BL10ScSn soleus preserved type-1 myofiber size and increased type-2A one, whereas EDL maintained adult values of total myofiber number and fiber-type composition. Mechanistically, curcumin only partially prevented the age-related changes in protein level and subcellular distribution of major costamere components and regulators. Conversely, it affected satellite cells, by maintaining adult levels of myofiber maturation in old regenerating soleus and increasing percentage of isolated, MyoD-positive satellite cells from old hindlimb muscles. Therefore, curcumin treatment successfully prevents presarcopenia and sarcopenia development by improving satellite cell commitment and recruitment.

Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy.

: Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s and recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies.

A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice.

Duchenne muscular dystrophy (DMD) is one of the most frequent and severe childhood muscle diseases. Its pathophysiology is multifaceted and still incompletely understood, but we and others have previously shown that oxidative stress plays an important role. In particular, we have demonstrated that inhibition of mitochondrial monoamine oxidases could improve some functional and biohumoral markers of the pathology. In the present study we report the use of dystrophic mdx mice to evaluate the efficacy of a dual monoamine oxidase B (MAO-B)/semicarbazide-sensitive amine oxidase (SSAO) inhibitor, PXS-5131, in reducing inflammation and fibrosis and improving muscle function. We found that a one-month treatment starting at three months of age was able to decrease reactive oxygen species (ROS) production, fibrosis, and inflammatory infiltrate in the tibialis anterior (TA) and diaphragm muscles. Importantly, we also observed a marked improvement in the capacity of the gastrocnemius muscle to maintain its force when challenged with eccentric contractions. Upon performing a bulk RNA-seq analysis, PXS-5131 treatment affected the expression of genes involved in inflammatory processes and tissue remodeling. We also studied the effect of prolonged treatment in older dystrophic mice, and found that a three-month administration of PXS-5131 was able to greatly reduce the progression of fibrosis not only in the diaphragm but also in the heart. Taken together, these results suggest that PXS-5131 is an effective inhibitor of fibrosis and inflammation in dystrophic muscles, a finding that could open a new therapeutic avenue for DMD patients.

Commitment of Autologous Human Multipotent Stem Cells on Biomimetic Poly-L-lactic Acid-Based Scaffolds Is Strongly Influenced by Structure and Concentration of Carbon Nanomaterial.

Nanocomposite scaffolds combining carbon nanomaterials (CNMs) with a biocompatible matrix are able to favor the neuronal differentiation and growth of a number of cell types, because they mimic neural-tissue nanotopography and/or conductivity. We performed comparative analysis of biomimetic scaffolds with poly-L-lactic acid (PLLA) matrix and three different p-methoxyphenyl functionalized carbon nanofillers, namely, carbon nanotubes (CNTs), carbon nanohorns (CNHs), and reduced graphene oxide (RGO), dispersed at varying concentrations. qRT-PCR analysis of the modulation of neuronal markers in human circulating multipotent cells cultured on nanocomposite scaffolds showed high variability in their expression patterns depending on the scaffolds' inhomogeneities. Local stimuli variation could result in a multi- to oligopotency shift and commitment towards multiple cell lineages, which was assessed by the qRT-PCR profiling of markers for neural, adipogenic, and myogenic cell lineages. Less conductive scaffolds, i.e., bare poly-L-lactic acid (PLLA)-, CNH-, and RGO-based nanocomposites, appeared to boost the expression of myogenic-lineage marker genes. Moreover, scaffolds are much more effective on early commitment than in subsequent differentiation. This work suggests that biomimetic PLLA carbon-nanomaterial (PLLA-CNM) scaffolds combined with multipotent autologous cells can represent a powerful tool in the regenerative medicine of multiple tissue types, opening the route to next analyses with specific and standardized scaffold features.