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Cited by 114Muscle Physiology and DisordersNutrition and Health in AgingS100 Proteins and Annexins

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Cellular and molecular mechanisms of sarcopenia: the S100B perspective

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Riuzzi, Francesca, Sorci, Guglielmo, Arcuri, Cataldo, Giambanco, Ileana, Bellezza, Ilaria, Minelli, Alba, Donato, Rosario·2018·Journal of Cachexia Sarcopenia and Muscle
DOI 10.1002/jcsm.12363PMC PMC6351675
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Abstract

Abstract Primary sarcopenia is a condition of reduced skeletal muscle mass and strength, reduced agility, and increased fatigability and risk of bone fractures characteristic of aged, otherwise healthy people. The pathogenesis of primary sarcopenia is not completely understood. Herein, we review the essentials of the cellular and molecular mechanisms of skeletal mass maintenance; the alterations of myofiber metabolism and deranged properties of muscle satellite cells (the adult stem cells of skeletal muscles) that underpin the pathophysiology of primary sarcopenia; the role of the Ca 2+ ‐sensor protein, S100B, as an intracellular factor and an extracellular signal regulating cell functions; and the functional role of S100B in muscle tissue. Lastly, building on recent results pointing to S100B as to a molecular determinant of myoblast–brown adipocyte transition, we propose S100B as a transducer of the deleterious effects of accumulation of reactive oxygen species in myoblasts and, potentially, myofibers concurring to the pathophysiology of sarcopenia.

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Figure 1 Schematic representation of cellular and molecular mechanisms driving adult myogenesis. Following acute (reversible) skeletal muscle injury serum factors (i.e. hormones and growth factors) and molecules passively released from damaged muscle tissue (e.g. DAMPs, among which S100B and HMGB1) or secreted by infiltrating proinflammatory (M1) and anti‐inflammatory/reparative (M2) macrophages (e.g. cytokines, S100B, and HMGB1), and components of the extracellular matrix participate in the activation of quiescent muscle SCs and their commitment to myoblasts, proliferation and/or differentiation into fusion‐competent myocytes, which form new myofibers and/or repair the damaged ones. It is not known whether S100B and/or HMGB1 can activate quiescent SCs. A minority of proliferating myoblasts return to a state of quiescence to replenish the SC reserve pool. Fibroblasts concur to the repair process by depositing extracellular matrix, but excess extracellular matrix deposition interferes with the regeneration process. Pericytes and IL‐4‐activated FAPs also participate in the regeneration process. DAMP, damage‐associated molecular pattern; FAPs, fibro/adipogenic precursors; IL‐4, interleukin‐4; SC, satellite cell.
Figure 1 Schematic representation of cellular and molecular mechanisms driving adult myogenesis. Following acute (reversible) skeletal muscle injury serum factors (i.e. hormones and growth factors) and molecules passively released from damaged muscle tissue (e.g. DAMPs, among which S100B and HMGB1) or secreted by infiltrating proinflammatory (M1) and anti‐inflammatory/reparative (M2) macrophages (e.g. cytokines, S100B, and HMGB1), and components of the extracellular matrix participate in the activation of quiescent muscle SCs and their commitment to myoblasts, proliferation and/or differentiation into fusion‐competent myocytes, which form new myofibers and/or repair the damaged ones. It is not known whether S100B and/or HMGB1 can activate quiescent SCs. A minority of proliferating myoblasts return to a state of quiescence to replenish the SC reserve pool. Fibroblasts concur to the repair process by depositing extracellular matrix, but excess extracellular matrix deposition interferes with the regeneration process. Pericytes and IL‐4‐activated FAPs also participate in the regeneration process. DAMP, damage‐associated molecular pattern; FAPs, fibro/adipogenic precursors; IL‐4, interleukin‐4; SC, satellite cell.CC BY-NC-ND · PubMed Central
Figure 2 Physical exercise and caloric restriction exert trophic/protective effects on skeletal muscles via several mechanisms. A moderate and balanced production of ROS is beneficial to muscle trophism. Green and light blue boxes/pathways refer to anabolic and/or antioxidant mechanisms leading to muscle structure/function preservation, enhanced insulin sensitivity, myofiber remodelling, and redox homeostasis. Pink boxes/pathways refer to catabolic mechanisms required for protein and organelle quality control and, hence, normal muscle trophism. However, hyperfunction of these pathways leads to muscle hypotrophy/atrophy. Released by exercising muscles, myokines (listed in the grey box; ↑ = increased release, ↓ = decreased release) exert either protective (e.g. IL‐1β, IL‐6, IL‐8, and decorin; magenta boxes and symbols) or detrimental (e.g. myostatin; pink boxes and symbols) effects on muscle trophism. ACVRs, activin A receptors; Akt, protein kinase B; AMP, adenosine monophosphate; AMPK, adenosine monophosphate kinase; ATGs, autophagy genes; eNOS, endothelial nitrix oxide synthase; IL‐1β and IL‐6 promote muscle trophism, stimulating glucose uptake and fatty acid (FA) oxidation. FOXO, forkhead box O; IGFR/IR, insulin growth factor receptor/insulin receptor; IL, interleukin; mTOR, mammalian target of rapamycin; NRF2, NF‐E2‐related factor 2; NO, nitrix oxide; NPRL2, Nitrogen permease regulator‐like 2; NT‐3, neutrophin 3; PGC‐1α, peroxisome proliferator‐activated receptor‐γ coactivator‐1α; PI3K, phosphoinositol‐3‐kinase; ROS, reactive oxygen species.
Figure 2 Physical exercise and caloric restriction exert trophic/protective effects on skeletal muscles via several mechanisms. A moderate and balanced production of ROS is beneficial to muscle trophism. Green and light blue boxes/pathways refer to anabolic and/or antioxidant mechanisms leading to muscle structure/function preservation, enhanced insulin sensitivity, myofiber remodelling, and redox homeostasis. Pink boxes/pathways refer to catabolic mechanisms required for protein and organelle quality control and, hence, normal muscle trophism. However, hyperfunction of these pathways leads to muscle hypotrophy/atrophy. Released by exercising muscles, myokines (listed in the grey box; ↑ = increased release, ↓ = decreased release) exert either protective (e.g. IL‐1β, IL‐6, IL‐8, and decorin; magenta boxes and symbols) or detrimental (e.g. myostatin; pink boxes and symbols) effects on muscle trophism. ACVRs, activin A receptors; Akt, protein kinase B; AMP, adenosine monophosphate; AMPK, adenosine monophosphate kinase; ATGs, autophagy genes; eNOS, endothelial nitrix oxide synthase; IL‐1β and IL‐6 promote muscle trophism, stimulating glucose uptake and fatty acid (FA) oxidation. FOXO, forkhead box O; IGFR/IR, insulin growth factor receptor/insulin receptor; IL, interleukin; mTOR, mammalian target of rapamycin; NRF2, NF‐E2‐related factor 2; NO, nitrix oxide; NPRL2, Nitrogen permease regulator‐like 2; NT‐3, neutrophin 3; PGC‐1α, peroxisome proliferator‐activated receptor‐γ coactivator‐1α; PI3K, phosphoinositol‐3‐kinase; ROS, reactive oxygen species.CC BY-NC-ND · PubMed Central
Figure 3 Extrinsic and intrinsic, cell‐autonomous factors concurring to determine changes in SCs with aging ultimately leading to reduced SCs' ability to maintain muscle mass (sarcopenia). Redox imbalance, due to either ROS overproduction or consequent to defective ROS removal, is a common trait of factors/lifestyle leading to cell senescence, reduction of SC self‐renewal, and muscle atrophy (refer to text). CDK, cyclin‐dependent kinase; FGF21, fibroblast growth factor 21; FOXO, forkhead box O; JAK/SAT, janus kinase/signal transducer and activator of transcription; MAPK, mitogen activated protein kinase; ROS, reactive oxygen species; SC, satellite cell.
Figure 3 Extrinsic and intrinsic, cell‐autonomous factors concurring to determine changes in SCs with aging ultimately leading to reduced SCs' ability to maintain muscle mass (sarcopenia). Redox imbalance, due to either ROS overproduction or consequent to defective ROS removal, is a common trait of factors/lifestyle leading to cell senescence, reduction of SC self‐renewal, and muscle atrophy (refer to text). CDK, cyclin‐dependent kinase; FGF21, fibroblast growth factor 21; FOXO, forkhead box O; JAK/SAT, janus kinase/signal transducer and activator of transcription; MAPK, mitogen activated protein kinase; ROS, reactive oxygen species; SC, satellite cell.CC BY-NC-ND · PubMed Central
Figure 4 Intracellular S100B levels dictate myoblast properties and fate. Oxidative stress leads to abnormally high levels of S100B in myoblasts via stimulation of NF‐κB activity. Accumulation of S100B under chronic oxidative conditions might be consequent to reduced p38 MAPK activity and reduced p38 MAPK‐driven S100B proteasomal degradation. Aged myoblasts show remarkably reduced ability to secrete S100B. Whether disulfide‐linked formation of S100B oligomers under oxidative conditions interferes with S100B release remains to be investigated (?). In turn, S100B activates NF‐κB with resultant up‐regulation of YY1 and down‐regulation of MyoD, and blockade of myogenic differentiation. S100B‐mediated NF‐κB activation also results in enhanced propensity of myoblasts to proliferate and to resist to apoptotic stimuli leading to reduced myogenic differentiation and reduced acquisition of quiescence. Although intracellular accumulation of S100B leads to defective p53 activity and uncontrolled proliferation in certain cell types (refer to text), no information is available regarding S100B's regulatory effects on p53 or p53‐induced cell senescence in myoblasts (?). Lastly, oxidative stress‐induced accumulation of S100B converts myoblasts into brown adipocytes via an NF‐κB/YY1/miR‐133 axis and NF‐κB/YY1/BMP7 axis. BMP7, bone morphogenetic protein 7; BMPR, bone morphogenetic factor receptor; ROS, reactive oxygen species; UCP‐1, uncoupling protein 1; YY1, Yin Yang 1.
Figure 4 Intracellular S100B levels dictate myoblast properties and fate. Oxidative stress leads to abnormally high levels of S100B in myoblasts via stimulation of NF‐κB activity. Accumulation of S100B under chronic oxidative conditions might be consequent to reduced p38 MAPK activity and reduced p38 MAPK‐driven S100B proteasomal degradation. Aged myoblasts show remarkably reduced ability to secrete S100B. Whether disulfide‐linked formation of S100B oligomers under oxidative conditions interferes with S100B release remains to be investigated (?). In turn, S100B activates NF‐κB with resultant up‐regulation of YY1 and down‐regulation of MyoD, and blockade of myogenic differentiation. S100B‐mediated NF‐κB activation also results in enhanced propensity of myoblasts to proliferate and to resist to apoptotic stimuli leading to reduced myogenic differentiation and reduced acquisition of quiescence. Although intracellular accumulation of S100B leads to defective p53 activity and uncontrolled proliferation in certain cell types (refer to text), no information is available regarding S100B's regulatory effects on p53 or p53‐induced cell senescence in myoblasts (?). Lastly, oxidative stress‐induced accumulation of S100B converts myoblasts into brown adipocytes via an NF‐κB/YY1/miR‐133 axis and NF‐κB/YY1/BMP7 axis. BMP7, bone morphogenetic protein 7; BMPR, bone morphogenetic factor receptor; ROS, reactive oxygen species; UCP‐1, uncoupling protein 1; YY1, Yin Yang 1.CC BY-NC-ND · PubMed Central
Figure 5 S100B is found to be associated with mitochondria in myoblasts. Proliferating L6 myoblasts91 show co‐localization of S100B (red signal) with the mitochondrial marker, cytochrome c (cytC; green signal). Shown is a merged image. Bar = 100 μm.
Figure 5 S100B is found to be associated with mitochondria in myoblasts. Proliferating L6 myoblasts91 show co‐localization of S100B (red signal) with the mitochondrial marker, cytochrome c (cytC; green signal). Shown is a merged image. Bar = 100 μm.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Riuzzi, F., Sorci, G., Arcuri, C., Giambanco, I., Bellezza, I., Minelli, A., & Donato, R.
Affiliations
University of Perugia (IT)
Corresponding author
Donato, Rosario
ORCID
Venue
Journal of Cachexia Sarcopenia and Muscle
Publisher
Wiley
Published
2018-11-30
Volume
9
Issue
7
Pages
1255-1268
ISSN
  • 2190-5991 (ISSN-L)
  • 2190-6009
DOI
10.1002/jcsm.12363
PMC
PMC6351675
OpenAlex
W2903461337
Cited by
114
References
152
Citations by year
2026: 7 · 2025: 17 · 2024: 22 · 2023: 16 · 2022: 17 · 2021: 13 · 2020: 16 · 2019: 5 · 2018: 1
FWCI
0.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cachexia Sarcopenia and Muscle (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fondazione Cassa di Risparmio di Perugia (2016‐0136.021, 2012.0241.021, 2015.0325.021)
  • Associazione Italiana per la Ricerca sul Cancro (17581)
  • French Muscular Dystrophy Association (16812, 12992)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
Keywords
sarcopenia, S100B, satellite cells, calcium-sensing proteins, reactive oxygen species, aging, muscle stem cells
MeSH terms
Humans, Biomarkers, Muscle, Skeletal, Muscle Fibers, Skeletal, Satellite Cells, Skeletal Muscle, Sarcopenia, S100 Calcium Binding Protein beta Subunit

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