Human Sarcopenic Myoblasts Can Be Rescued by Pharmacological Reactivation of HIF-1α

Cirillo, Federica; Mangiavini, Laura; Rocca, Paolo La; Piccoli, Marco; Ghiroldi, Andrea; Rota, Paola; Tarantino, Adriana; Canciani, Barbara; Coviello, Simona; Messina, Carmelo; Ciconte, Giuseppe; Pappone, Carlo; Peretti, Giuseppe M.; Anastasia, Luigi

doi:10.3390/ijms23137114

Cited by 8 publications

(5 citation statements)

References 44 publications

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“…We will further validate the therapeutic efficacy of vorinostat in aged mice, a common disease model for sarcopenia. Moreover, human-derived myoblasts serve as a superior experimental model for sarcopenia [59,60]; their use may yield a more accurate and reliable evidence base for the clinical translation of repurposed drugs. The etiology of sarcopenia is complex and not fully understood, with mitochondrial dysfunction, inflammation, satellite cell dysfunction, and oxidative stress, potentially contributing to sarcopenia risk [61].…”

Section: Discussionmentioning

confidence: 99%

Repurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans

et al. 2023

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Sarcopenia, characterized by age-related loss of muscle mass, strength, and decreased physical performance, is a growing public health challenge amid the rapidly ageing population. As there are no approved drugs that target sarcopenia, it has become increasingly urgent to identify promising pharmacological interventions. In this study, we conducted an integrative drug repurposing analysis utilizing three distinct approaches. Firstly, we analyzed skeletal muscle transcriptomic sequencing data in humans and mice using gene differential expression analysis, weighted gene co-expression analysis, and gene set enrichment analysis. Subsequently, we employed gene expression profile similarity assessment, hub gene expression reversal, and disease-related pathway enrichment to identify and repurpose candidate drugs, followed by the integration of findings with rank aggregation algorithms. Vorinostat, the top-ranking drug, was also validated in an in vitro study, which demonstrated its efficacy in promoting muscle fiber formation. Although still requiring further validation in animal models and human clinical trials, these results suggest a promising drug repurposing prospect in the treatment and prevention of sarcopenia.

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Section: Discussionmentioning

confidence: 99%

Repurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans

et al. 2023

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“…To corroborate the results for the role of HIF-1α and MMP-9 on myogenic activation and commitment, we investigated some typical electrophysiological functional features of sarcolemma that better characterize an activated/committed myoblast (Figure 9). 100 µm 2 for each confocal stack (10). a.u.…”

Section: Functional Electrophysiological Analysesmentioning

confidence: 99%

“…In particular, proliferating myoblasts produce energy mainly through glycolysis, which is different to myotubes which exhibit a major aerobic capacity [7][8][9]. Several papers highlighted the hypoxia-inducible factor (HIF)-1α as a regulator of myogenesis and SCs/myoblasts' homeostasis in vitro and in vivo [10][11][12][13][14][15][16][17][18][19][20][21][22]. It is a dimeric, basic helix-loop-helix PER-ARNT-SIM transcriptional factor composed of a HIF-1β subunit that is constitutively expressed and a HIF-1α (or its paralogs HIF-2α and HIF-3α) subunit that is oxygen sensitive.…”

Section: Introductionmentioning

confidence: 99%

“…Here, the HIF-1α subunit assembles a transcriptional complex with HIF-1β which is able to interact with different coactivators and to modulate the expression of several target genes implied in many cellular processes comprising the regulation of glycolytic metabolism in skeletal muscle [15,[23][24][25]. However, in skeletal muscle tissue and myoblasts/SCs, an oxygen level-independent regulation of the expression and activation of HIF-1α has been reported, thus suggesting a role of such a protein in skeletal muscle physiological functions and homeostasis [10,18,21,22,[26][27][28][29][30][31]. Nevertheless, some controversy remains about HIF-1α's spatio-temporal expression and on its exact role in myoblasts during myogenic differentiation.…”

Section: Introductionmentioning

confidence: 99%

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HIF-1α/MMP-9 Axis Is Required in the Early Phases of Skeletal Myoblast Differentiation under Normoxia Condition In Vitro

Chellini,

Tani,

Parigi

et al. 2023

Cells

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Hypoxia-inducible factor (HIF)-1α represents an oxygen-sensitive subunit of HIF transcriptional factor, which is usually degraded in normoxia and stabilized in hypoxia to regulate several target gene expressions. Nevertheless, in the skeletal muscle satellite stem cells (SCs), an oxygen level-independent regulation of HIF-1α has been observed. Although HIF-1α has been highlighted as a SC function regulator, its spatio-temporal expression and role during myogenic progression remain controversial. Herein, using biomolecular, biochemical, morphological and electrophysiological analyses, we analyzed HIF-1α expression, localization and role in differentiating murine C2C12 myoblasts and SCs under normoxia. In addition, we evaluated the role of matrix metalloproteinase (MMP)-9 as an HIF-1α effector, considering that MMP-9 is involved in myogenesis and is an HIF-1α target in different cell types. HIF-1α expression increased after 24/48 h of differentiating culture and tended to decline after 72 h/5 days. Committed and proliferating mononuclear myoblasts exhibited nuclear HIF-1α expression. Differently, the more differentiated elongated and parallel-aligned cells, which are likely ready to fuse with each other, show a mainly cytoplasmic localization of the factor. Multinucleated myotubes displayed both nuclear and cytoplasmic HIF-1α expression. The MMP-9 and MyoD (myogenic activation marker) expression synchronized with that of HIF-1α, increasing after 24 h of differentiation. By means of silencing HIF-1α and MMP-9 by short-interfering RNA and MMP-9 pharmacological inhibition, this study unraveled MMP-9’s role as an HIF-1α downstream effector and the fact that the HIF-1α/MMP-9 axis is essential in morpho-functional cell myogenic commitment.

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“…In addition, a pharmacological activation of HIF-1α and its target genes caused a reduction in skeletal muscle atrophy and activation of PAX7 gene expression. Thus, HIF-1α plays a role in sarcopenia and is involved in satellite cell homeostasis but need further research [ 57 ] ( Figure 4 ).…”

Section: Different Pathophysiological Mechanisms Of Hif-1α In Renal D...mentioning

confidence: 99%

The Role of Hypoxia-Inducible Factor-1 Alpha in Renal Disease

Liu

Xiong

2022

Molecules

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Partial pressure of oxygen (pO2) in the kidney is maintained at a relatively stable level by a unique and complex functional interplay between renal blood flow, glomerular filtration rate (GFR), oxygen consumption, and arteriovenous oxygen shunting. The vulnerability of this interaction renders the kidney vulnerable to hypoxic injury, leading to different renal diseases. Hypoxia has long been recognized as an important factor in the pathogenesis of acute kidney injury (AKI), especially renal ischemia/reperfusion injury. Accumulating evidence suggests that hypoxia also plays an important role in the pathogenesis and progression of chronic kidney disease (CKD) and CKD-related complications, such as anemia, cardiovascular events, and sarcopenia. In addition, renal cancer is linked to the deregulation of hypoxia pathways. Renal cancer utilizes various molecular pathways to respond and adapt to changes in renal oxygenation. Particularly, hypoxia-inducible factor (HIF) (including HIF-1, 2, 3) has been shown to be activated in renal disease and plays a major role in the protective response to hypoxia. HIF-1 is a heterodimer that is composed of an oxygen-regulated HIF-1α subunit and a constitutively expressed HIF-1β subunit. In renal diseases, the critical characteristic of HIF-1α is protective, but it also has a negative effect, such as in sarcopenia. This review summarizes the mechanisms of HIF-1α regulation in renal disease.

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Human Sarcopenic Myoblasts Can Be Rescued by Pharmacological Reactivation of HIF-1α

Cited by 8 publications

References 44 publications

Repurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans

Repurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans

HIF-1α/MMP-9 Axis Is Required in the Early Phases of Skeletal Myoblast Differentiation under Normoxia Condition In Vitro

The Role of Hypoxia-Inducible Factor-1 Alpha in Renal Disease

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