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Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review)

  • Authors:
    • Qingchen Li
    • Haoyang Gao
    • Xiaotong Ma
    • Ze Wang
    • Linlin Zhao
    • Weihua Xiao
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    Affiliations: Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 129
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    Published online on: June 27, 2025
       https://doi.org/10.3892/ijmm.2025.5570
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Abstract

The cardiovascular and musculoskeletal systems are two core systems essential for maintaining human physiological functions and their dynamic interactions play a critical role in overall health. Exosomes, nanosized vesicles released by cells, contain bioactive substances including microRNA, long non‑coding RNA, lipids and proteins and participate in the pathophysiological regulation of multiple organ systems by mediating intercellular communication. Bone‑derived exosomes ameliorate cardiovascular diseases through the regulation of oxidative stress, inflammatory responses and apoptosis. Conversely, cardiovascular‑derived exosomes enhance bone homeostasis by suppressing osteoclast activity or promoting osteogenic differentiation, but they may also exacerbate pathological progression in conditions such as osteoarthritis. Skeletal muscle‑derived exosomes protect cardiomyocytes in muscular dystrophy through functional molecules delivery. However, under pathological conditions such as sarcopenia, skeletal muscle‑derived exosomes may aggravate cardiac dysfunction by activating pro‑apoptotic signals. Similarly, cardiovascular‑derived exosomes exhibit dual roles in skeletal muscle regulation, promoting regeneration while potentially inducing atrophy during heart failure. In addition, exosomes demonstrate significant clinical value as diagnostic biomarkers and targeted drug delivery vehicles, both for early disease detection and regenerative therapies. The present review systematically outlined the mechanisms underlying exosome‑mediated bidirectional crosstalk between the cardiovascular and musculoskeletal systems and explores their clinical application potential. It provided theoretical insights and novel perspectives for further research into the pathogenesis and therapeutic strategies of cardiovascular and musculoskeletal diseases.
View Figures

Figure 1

Biogenesis and cargo composition of
exosomes. Initially, the plasma membrane invaginates, leading to
the formation of early endosomes in the cytoplasm. These mature
into late endosomes and a second invagination generates MVBs
containing ILVs, which will eventually become exosomes. MVBs can
fuse with lysosomes for degradation or release exosomes through
exocytosis. Exosomes are composed of diverse proteins, including
tetraspanins, adhesion molecules, cytoskeletal proteins, heat shock
proteins, membrane transport proteins as well as nucleic acids such
as mRNA, DNA and miRNAs, along with various lipids and enzymes.
MVBs, multivesicular bodies; ILVs, intraluminal vesicles;
miR/miRNAs, microRNAs; HSP, heat shock protein; ESCRT, endosomal
sorting complex required for transport; TSG101, tumor
susceptibility gene 101; GAPDH, glyceraldehyde-3-phosphate
dehydrogenase; Alix, apoptosis-linked gene 2-interacting protein X;
TGF-β, transforming growth factor β; TNF-α, tumor necrosis
factor-α; TRAIL, tumor necrosis factor-related apoptosis-inducing
ligand.

Figure 2

BMSC-Exos ameliorate MI. miR-214,
miR-181a-5p and miR-21 in BMSC-Exos can inhibit CaMKII and ATF2
expression, respectively and regulate the PTEN/PI3K/AKT axis,
resulting in downregulation of ROS and MDA expression upregulation
of SOD and then inhibit MI oxidative stress. In addition,
miR-182-5p and other molecules in BMSC-Exos can inhibit MI
inflammation by suppressing the TLR4/NF-κB pathway, reducing LOX-1
and NLRP3 inflammasome expression, regulating macrophage
polarization, or activating the Nrf2/HO-1 axis, thereby suppressing
the release of pro-inflammatory factors while upregulating
anti-inflammatory cytokines IL-10 expression. BMSC-derived exosomal
miR-125b-5p and miR-301 can suppress p53/Bnip3 signaling, reduce
the LC3-II/I ratio and inhibit excessive autophagy. BMSC-Exos can
also promote the expression of Beclin-1, ATG13 and LC3-II, while
decreasing P62 gene expression to enhance protective autophagy,
improving MI. Notably, miR-210, miR-338 and miR-144 in BMSC-Exos
can inhibit AIFM3/P53, PI3K/AKT, MAP3K2/JNK and PTEN/AKT signaling
pathways, while BMSC-Exos with low expression of miR-153-3p can
activate ANGPT1-mediated VEGF/PI3K/AKT/eNOS signaling, thereby
inhibiting apoptosis. ITCH carried by BMSC-Exos enhances ASK1
ubiquitination and degradation. BMSC-Exos containing lncRNA-UCAI,
miR-125b-5p and others can upregulate miR-24 in CMCs and inhibit
apoptosis via the miR-873-5p/XIAP axis, exerting cardioprotective
effects. miR-29b-3p and miR-411 in BMSC-Exos target and inhibit
ADAMTS16 and HIF-1α, enhance VEGF secretion and increase capillary
density, thereby promoting angiogenesis after MI. miR-19a/19b,
miR-129-5p, miR-1180-3p and other molecules in BMSC-Exos can
inhibit EZH2 to promote HMGA2 expression and activate the PI3K/AKT
pathway, or inhibit ETS1 signaling to downregulate collagen I,
collagen III and TGF-β1, alleviating cardiac fibrosis. BMSC-Exos,
bone marrow mesenchymal stem cell-derived exosomes; MI, myocardial
infarction; miR/miRNA, microRNA; CaMKII,
calcium-calmodulin-dependent protein kinase II; ATF2, activating
transcription factor 2; PTEN, phosphatase and tensin homolog
deleted on chromosome ten; PI3K, phosphatidylinositol 3-kinase;
AKT, protein kinase B; ROS, reactive oxygen species; MDA,
malondialdehyde; SOD, superoxide dismutase; TLR4, toll-like
receptor 4; NF-κB, nuclear factor-κB; LOX-1, lectin-like oxidized
low-density lipoprotein receptor-1; NLRP3, nucleotide-binding
domain and leucine-rich repeat pyrin domain-containing-3; Nrf2,
nuclear factor erythroid 2-related factor 2; HO-1, heme
oxygenase-1; Bnip3, Bcl-2/adenovirus E1B 19-kDa interacting protein
3; LC3-II, microtubule-associated protein 1 light chain 3-II;
Beclin-1, Bcl-2-interacting protein 1; ATG13, autophagy-related
protein 13; AIFM3, apoptosis-inducing factor,
mitochondrion-associated 3; MAP3K2, mitogen-activated protein
kinase kinase kinase 2; JNK, c-Jun N-terminal kinase; ANGPT1,
angiopoietin 1; VEGF, vascular endothelial growth factor; eNOS,
endothelial nitric oxide synthase; ITCH, itchy E3 ubiquitin ligase;
ASK1, apoptosis signal-regulated kinase-1; ADAMTS16, a
disintegrin-like metalloproteinase with thrombospondin motifs-16;
HIF-1α, hypoxia-inducible factor-1; EZH2, enhancer of zeste 2
polycomb repressive complex 2 subunit; HMGA2, high mobility group
AT-hook 2; ETS1, ETS proto-oncogene 1; TGF-β1, transforming growth
factor-β1.

Figure 3

BMSC-Exos alleviate MIRI.
miR-101a-3p, miR-149-5p and let-7c-5p in BMSC-Exos can activate the
PI3K/AKT signaling pathway or inhibit Faslg, further activating the
Wnt/β-catenin pathway, enhancing SOD activity and reducing ROS, MDA
and LDH levels. BMSC-derived exosomal lncRNA A2M-AS1 can target
miR-556-5p and upregulate XIAP expression, alleviating oxidative
damage. BMSC-Exos can also activate the HAND2-AS1/miR-17-5p/Mfn2
pathway to reduce H/R-induced myocardial injury. miR-98-5p in
BMSC-Exos suppresses cardiac inflammation by inhibiting TLR4
expression and activating the PI3K/AKT pathway. BMSC-derived
exosomal miR-25-3p, miR-182 and miR-21-5p can inhibit JAK2/STAT3
and TLR4/NF-κB signaling while targeting the TLR4/PI3K/AKT pathway,
promoting macrophage polarization toward the M2 phenotype. Notably,
KLF13 is one of the target genes of miR-125a-5p in BMSC-Exos that
promotes M2 macrophage polarization, downregulating IL-6, IL-1β and
TNF-α expression and upregulating IL-10 expression to suppress
inflammation and improve MIRI. miR-125b, miR-183-5p, miR-486-5p,
lncRNA HCP5 and miR-19a in BMSC-Exos inhibit SIRT7, FOXO1 and
regulate miR-497/IGF1/PI3K/AKT or PTEN/AKT/ERK signaling pathways,
downregulating Bax, caspase-3, cleaved-caspase-3 and upregulating
Bcl-2 to inhibit MIRI apoptosis. In addition, the lncRNA Mir9-3hg
in BMSC-Exos can alleviate ferroptosis by downregulating ACSL4
expression and upregulating GPX4 and GSH expression through the
Pum2/PRDX6 axis. miR-330-3p in BMSC-Exos targets and inhibits BAP1
to regulate the SLC7A11/IP3R pathway and suppress mPTP opening,
thereby inhibiting ferroptosis. BMSC-Exos, bone marrow mesenchymal
stem cell-derived exosomes; MIRI, myocardial ischemia-reperfusion
injury; miR/miRNA, microRNA; PI3K, phosphatidylinositol 3-kinase;
AKT, protein kinase B; Faslg, fas ligand gene; SOD, superoxide
dismutase; ROS, reactive oxygen species; MDA, malondialdehyde; LDH,
lactate dehydrogenase; lncRNA, long non-coding RNA; XIAP, X-linked
inhibitor of apoptosis protein; Mfn2, mitofusin 2 protein; H/R,
hypoxia/reoxygenation; TLR4, toll-like receptor 4; JAK2, Janus
kinase 2; STAT3, signal transducer and activator of transcription
3; NF-κB, nuclear factor-κB; KLF13, Krüppel-like transcription
factor 13; TNF-α, tumor necrosis factor-α; SIRT7, sirtuin 7; FOXO1,
forkhead box transcription factor 1; IGF1, insulin-like growth
factor 1; PTEN, phosphatase and tensin homolog deleted on
chromosome ten; ERK, extracellular signal-regulated kinase; Bax,
Bcl-2 associated X protein; ACSL4, Acyl-CoA synthetase long-chain
family member 4; GPX4, glutathione peroxidase 4; GSH, glutathione;
Pum2, RNA-binding protein Pumilio2; PRDX6, peroxiredoxin 6; BAP1,
BRCA1-associated protein 1; SLC7A11, solute carrier family 7a
member 11; IP3R, inositol 1,4,5-trisphosphate receptor; mPTP,
mitochondrial permeability transition pore.

Figure 4

BMSC-Exos improve AS. miR-512-3p and
lncRNA FENDRR delivered by BMSC-Exos can inhibit Keap1 and
upregulate Nrf2 expression, or interact with miR-28 to regulate
TEAD1 expression, respectively, thereby inhibiting AS apoptosis,
inflammation and oxidative stress, which alleviates endothelial
dysfunction. miR-let7 in BMSC-Exos can inhibit the HMGA2/NF-κB and
IGF2BP1/PTEN signaling pathways, promoting M2 macrophage
polarization and suppressing plaque infiltration. Knockdown of
LOC100129516 in BMSC-Exos can activate the PPARγ/LXRα/ABCA1
pathway, enhancing cholesterol efflux from THP-1 macrophage-derived
foam cells. miR-223 and lncRNA AU020206 in BMSC-Exos can directly
inhibit NLRP3 expression or suppress the CEBPB/NLRP3 axis,
downregulating caspase-1 and GSDMD expression and reducing the
release of IL-1β and IL-18, thereby inhibiting AS macrophage
pyroptosis. BMSC-Exos, bone marrow mesenchymal stem cell-derived
exosomes; AS, atherosclerosis; miR/miRNA, microRNA; lncRNA, long
non-coding RNA; Keap1, Kelch-like ECH-associated protein 1; Nrf2,
nuclear factor erythroid 2-related factor 2; TEAD1, TEA domain
transcription factor 1; HMGA2, high mobility group AT-hook 2;
NF-κB, nuclear factor-κB; IGF2BP1, insulin-like growth factor 2
mRNA-binding protein 1; PTEN, phosphatase and tensin homolog
deleted on chromosome ten; PPARγ, proliferator-activated receptor
γ; LXRα, liver X receptor α; ABCA1, ATP-binding cassette
transporter A1; NLRP3, nucleotide-binding domain and leucine-rich
repeat pyrin domain-containing-3; CEBPB, CCAAT/enhancer-binding
protein beta; GSDMD, gasdermin-D.

Figure 5

BMSC-Exos ameliorate other CVDs. (A)
BMSC-Exos alleviate DIC. miR-96 carried by BMSC-Exos targets and
inhibits the Rac1/NF-κB signaling axis, suppressing oxidative
stress and inflammation. lncRNA MSTRG.58791.2 in BMSC-Exos can
inhibit inflammation. BMSC-Exos can also regulate the
PI3K/AKT/FOXO1 and HMGB1/TLR4/NLRP3 pathways, reducing GSDMD
expression and inhibiting DOX-induced CMCs pyroptosis and oxidative
stress. lncRNA GHET1 in BMSC-Exos targets IGF2BP1 to reduce NLRP3
mRNA stability, ameliorating DOX-induced CMCs pyroptosis. (B)
BMSC-Exos mitigate HF. BMSC-Exos can exert anti-fibrotic effects,
inhibit CMCs hypertrophy and suppress inflammation by inducing
myofibroblast senescence, inhibiting the Hippo-YAP signaling axis,
or enhancing KLF4 expression. (C) BMSC-Exos improve AF.
Nrf2-overexpressing BMSC-Exos can reduce cardiac fibrosis through
the Nrf2/HO-1 pathway. miR-148a carried by BMSC-Exos targets and
binds to SMOC2 mRNA to inhibit its expression, thereby suppressing
CMCs apoptosis. (D) BMSC-Exos alleviate sepsis-induced myocardial
dysfunction. CircRTN4, miR-34a-5p and miR-141 carried by BMSC-Exos
can inhibit CMCs apoptosis by interacting with miR-497-5p to
upregulate MG53, regulating the HMGB1/AMPK signaling pathway to
reduce CMCs pyroptosis and binding and inhibiting PTEN expression
to activate the β-catenin signaling axis, thereby alleviating
inflammation and CMCs apoptosis. BMSC-Exos, bone marrow mesenchymal
stem cell-derived exosomes; CVDs, cardiovascular diseases; DIC,
doxorubicin-induced cardiomyopathy; miR/miRNA, microRNA; Rac1,
ras-related C3 botulinum toxin substrate 1; NF-κB, nuclear
factor-κB; lncRNA, long non-coding RNA; PI3K, phosphatidylinositol
3-kinase; AKT, protein kinase B; FOXO1, forkhead box transcription
factor 1; HMGB1, high mobility group box 1; TLR4, toll-like
receptor 4; NLRP3, nucleotide-binding domain and leucine-rich
repeat pyrin domain-containing-3; GSDMD, gasdermin-D; DOX,
doxorubicin; CMCs, cardiomyocytes; IGF2BP1, insulin-like growth
factor 2 mRNA-binding protein 1; HF, heart failure; KLF4,
Krüppel-like factor 4; AF, atrial fibrillation; Nrf2, nuclear
factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; SMOC2,
secreted modular calcium-binding protein 2; circRNA, circular RNA;
MG53, mitsugumin 53; AMPK, AMP-activated protein kinase; PTEN,
phosphatase and tensin homolog deleted on chromosome ten.

Figure 6

Cardiovascular-derived exosomes
regulate the bone. Cardiovascular-derived exosomes exhibit a dual
role in regulating skeletal diseases. Positive regulation:
Cardiovascular-derived exosomal miR-155 and miR-3p-975_4191 can
inhibit osteoclast activity and reduce bone resorption, inhibit TNF
to regulate BMSC differentiation, suppress adipogenic
differentiation and promote osteogenic differentiation to prevent
the development of osteoporosis. Cardiovascular-derived exosomes
can also inhibit osteoblast suppression by suppressing ferritin
autophagy-dependent ferroptosis. Cardiovascular-derived exosomal
miR-27a and other molecules can activate the MAPK/ERK pathway to
promote BMSC osteoblast differentiation and inhibit adipogenic
differentiation, or directly target DKK2 and activate the
Wnt/β-catenin signaling pathway to promote bone formation and
improve femoral head necrosis. Moreover, miR-133a, miR-208a,
miR-499-5p and other miRNAs in cardiovascular-derived exosomes can
target bone marrow mononuclear cells, downregulating CXCR4
expression and mobilize progenitor cells to participate in bone
remodeling. Negative regulation: Cardiovascular-derived exosomes
reduce chondrocyte resistance to oxidative stress and induce
apoptosis by inhibiting autophagy and p21 expression, thus
promoting the progression of OA. Cardiovascular-derived exosomes
can act on mesenchymal stem cells, accelerating BMSC damage in MI
heart transplants. miR/miRNA, microRNA; TNF, tumor necrosis factor;
BMSC, bone marrow mesenchymal stem cell; MAPK, mitogen-activated
protein kinases; ERK, extracellular signal-regulated kinase; DKK2,
dikkopf 2; CXCR4, CXC motif chemokine receptor type 4; OA,
osteoarthritis; MI, myocardial infarction.

Figure 7

Exosome-mediated crosstalk between
skeletal muscle and cardiovascular system. Skeletal muscle and
cardiovascular system exhibit both positive and negative regulatory
crosstalk mediated by exosomes. Positive regulation: Skeletal
muscle-derived exosomes contain myokine and musclin that can
inhibit cardiopulmonary heart failure. Skeletal muscle-derived
exosomes can promote the expression of Cx43 in ventricular
myocardium, enhance I/R ventricular conduction and inhibit
inflammation and apoptosis to improve cardiac function in DMD mice.
Cardiovascular-derived exosomal miR-148a promotes muscle
regeneration, while AT1R modulates skeletal muscle vascular
responses to neurohormonal stimulation. Cardiovascular-derived
exosomes can also promote muscle regeneration and the restoration
of contractile force. Negative regulation: Skeletal muscle-derived
exosomes rich in miR-16-5p directly inhibit SESN1 transcription,
leading to mTOR signaling upregulation, promoting CMCs apoptosis
and exacerbating repair impairment after myocardial infarction.
Cardiovascular-derived exosomal miR-1 and miR-133 can promote
muscle atrophy. Cx43, connexin 43; I/R, ischemia/reperfusion; DMD,
Duchenne muscular dystrophy; miR/miRNA, microRNA; AT1R, angiotensin
II type I receptor; SESN1, sestrin 1; CMCs, cardiomyocytes; mTOR,
mechanistic target of rapamycin; MI, myocardial infarction.
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Li Q, Gao H, Ma X, Wang Z, Zhao L and Xiao W: Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review). Int J Mol Med 56: 129, 2025.
APA
Li, Q., Gao, H., Ma, X., Wang, Z., Zhao, L., & Xiao, W. (2025). Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review). International Journal of Molecular Medicine, 56, 129. https://doi.org/10.3892/ijmm.2025.5570
MLA
Li, Q., Gao, H., Ma, X., Wang, Z., Zhao, L., Xiao, W."Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review)". International Journal of Molecular Medicine 56.3 (2025): 129.
Chicago
Li, Q., Gao, H., Ma, X., Wang, Z., Zhao, L., Xiao, W."Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review)". International Journal of Molecular Medicine 56, no. 3 (2025): 129. https://doi.org/10.3892/ijmm.2025.5570
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Spandidos Publications style
Li Q, Gao H, Ma X, Wang Z, Zhao L and Xiao W: Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review). Int J Mol Med 56: 129, 2025.
APA
Li, Q., Gao, H., Ma, X., Wang, Z., Zhao, L., & Xiao, W. (2025). Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review). International Journal of Molecular Medicine, 56, 129. https://doi.org/10.3892/ijmm.2025.5570
MLA
Li, Q., Gao, H., Ma, X., Wang, Z., Zhao, L., Xiao, W."Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review)". International Journal of Molecular Medicine 56.3 (2025): 129.
Chicago
Li, Q., Gao, H., Ma, X., Wang, Z., Zhao, L., Xiao, W."Exosome‑mediated crosstalk between the cardiovascular and musculoskeletal systems: Mechanisms and therapeutic potential (Review)". International Journal of Molecular Medicine 56, no. 3 (2025): 129. https://doi.org/10.3892/ijmm.2025.5570
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