Table 1.

Disrupted signaling pathways in DMD muscles and surrounding tissues

	Signaling pathway	Up- (↑) or downregulated (↓) in DMD	Short description	References for further reading
Muscle inflammation	TLRs	↑	Toll-like receptors (TLRs) belong to the pattern recognition receptors and play crucial roles in the innate immune response. After interaction with damage-associated molecules patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), TLRs initiate downstream signaling to activate NF-κB, interferons, or mitogen-activated protein kinases (MAPKs) that regulate the expression of immune defense-related genes	[75, 244]
	MyD88	↑	Myeloid differentiation primary response 88 (MyD88) is an adaptor protein for inflammatory signaling pathways, downstream of TLRs and IL-1 receptors. MyD88 links TLRs or IL-1 receptors to IL-1R-associated kinase (IRAK), while activation of IRAK activates NF-κB, MAPKs, and activator protein 1, driving immune response	[245]
	NF-κB	↑	Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of inducible transcription factors regulating multiple aspects of immune response and inflammation. NF-κB promotes the expression of proinflammatory genes and regulates the survival, activation, and differentiation of immune cells	[246, 247]
	AP-1	↑	Activator protein 1 (AP-1) is a heterodimer transcription factor built of proteins that belong to the Fos, Jun, ATF, and MAF families. In response to growth factor and cytokine signaling, AP-1 controls a wide range of cellular processes, including cell proliferation, death, survival, and differentiation	[248, 271]
	MMPs	↑	Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases involved in extracellular matrix remodeling, both during physiological processes and in pathological conditions. MMPs are also important players during inflammation	[249]
	TNF	↑	Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that regulates a number of signaling pathways with various downstream effects. TNF proteins are predominantly expressed by immune cells. TNF signaling impacts immune response, inflammation, cell proliferation, programmed cell death, and necrosis	[250]
	Klotho	↓	Klotho proteins are obligate components of endocrine fibroblast growth factor (FGF) receptor complexes and provide the high-affinity binding of FGF19, FGF21, and FGF23 to their receptors. Klotho proteins are known to play a role in aging-related diseases, diabetes, cancer, arteriosclerosis, renal and bone disease, and inflammation processes	[251]
	TGF-β	↑	Transforming growth factor-β (TGF-β) initiates signaling through the canonical SMAD pathway, regulating the expression of hundreds of genes. TGF-β induces also various noncanonical pathways that are responsible for cytoskeleton organization, cell polarity, and miRNA maturation. The effects of TGF-β signaling depend on the cellular context	[252]
	IL	↑	Interleukins (ILs) are a group of cytokines with immunomodulatory functions that play an important role in immune cell differentiation and activation. ILs could have pro- and anti-inflammatory effects, depending on the producing and responding cell type or the phase of the immune response	[253]
Muscle – bone	Wnt/β-cat	↑	Wnt/β-catenin (Wnt/β-cat) pathway regulates cell fate determination, cell migration, polarity and organogenesis during embryogenesis. Binding of Wnt to its membrane receptor causes translocation of β-cat degradation complex to the cell membrane, effecting in accumulation of β-cat in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator	[272]
	OPN	↑	Osteopontin (OPN) is a multifunctional protein involved in physiological processes and the pathogenesis of various diseases (e.g., atherosclerosis, cancer, chronic inflammatory diseases). OPN interacts with several integrins and therefore controls cell migration, adhesion, and survival. Additionally, OPN promotes inflammation and regulates biomineralization	[254]
	RANK/RANKL/OPG	↑	Receptor activator of NF-κB (RANK), its ligand (RANKL), and osteoprotegerin (OPG) form the triad of the ligand/signaling receptor/decoy receptor. RANKL, RANK, and OPG have pivotal roles in the regulation of bone metabolism and the immune system. The triad is involved in diverse physiological and pathological contexts, including muscle metabolism	[255]
	IL-6	↑	Interleukin 6 (IL-6) can act both as a pro-inflammatory cytokine and an anti-inflammatory myokine, depending on the cellular context. Additionally, IL-6 stimulates osteoclastogenesis	[78, 256]
	LIF	↑	Leukemia inhibitory factor (LIF) is an IL-6 class cytokine involved in controlling stem cell pluripotency, differentiation, bone metabolism, and inflammation. LIF signaling activates the JAK/STAT, MAPK, and PI3K pathways. This pleiotropic cytokine elicits a varied response in different cell types	[257]
	POSTN	↑	Periostin (POSTN) is an extracellular matrix protein that acts as a structural molecule of the bone matrix and a signaling molecule that stimulates osteoblasts through integrin receptors and the Wnt/β-cat pathway. POSTN is secreted in muscles during regeneration and differentiation	[258]
	FGF21	↑	Fibroblast growth factor 21 (FGF21) is a hormone produced by several tissues that controls various metabolic pathways. Muscle-derived FGF21 acts as a stress-induced myokine, found to promote muscle atrophy and bone loss	[259]
Muscle—microvasculature	NOS, NO	↓	Nitric oxide synthases (NOSs) catalyze the production of nitric oxide (NO) from L-arginine that controls, among others, vasodilation, and angiogenesis. NO also activates guanylyl cyclases (GC), which synthesize the second messenger cyclic guanosine monophosphate (cGMP), and act on its downstream targets, such as cGMP-activated protein kinase (PKG) or cyclic nucleotide-activated ion channels	[260]
	VEGF	↓	Vascular endothelial growth factors (VEGFs) are key regulators of vascular development and of blood vessel function. Binding of VEGF to the VEGF receptor initiates the downstream signaling cascade and ultimately results in cell proliferation, migration, and the three-dimensional arrangement to form a vascular tube	[261]
	miR-206	↑	Micro-RNA miR-206 is expressed specifically in skeletal muscles. miR-206 impedes cell proliferation and promotes SC and myoblast differentiation via posttranscriptional regulation of gene expression, boosting muscle regeneration and growth	[262]
	HIF-1α	↓	HIF-1α is a regulatory subunit of hypoxia-inducible factor-1 (HIF-1), an oxygen-dependent transcriptional activator. Target genes of HIF-1 are related to angiogenesis, cell proliferation and survival	[263]
Muscle—neuron	MuSK	↓	Muscle-specific kinase (MuSK) is a transmembrane tyrosine kinase that forms a multiprotein complex localized in the postsynaptic sarcolemma. In response to neural agrin signaling, autophosphorylation of MuSK drives intracellular signaling cascades to coordinate the local synthesis and assembly of synaptic proteins. It results in the reorganization of the cytoskeleton and the recruitment of AChR-binding scaffolding proteins to aggregate AChRs	[160]
	AChR	Defects in clustering	Acetylcholine receptors (AChRs) are ligand-gated ion channels that open upon acetylcholine binding and induce postsynaptic depolarization. AChR clustering is necessary for the proper functioning of the neuromuscular junction	[264]
	Utrophin	↑	Utrophin is a dystrophin homolog. Similar to dystrophin, utrophin presents mechanical functions and forms a signaling hub as a scaffold for various proteins. The upregulation of utrophin gene (UTRN) is one of the potential strategies to treat DMD	[265]
Muscle satellite cells	MARK2	↓	Microtubule affinity regulating kinase 2 (MARK2) is a serine/threonine-protein kinase that is an important regulator of cell polarity. MARK2 modulates microtubule network via phosphorylation and inactivation of microtubule-associating proteins	[46, 266]
	PARD3	Loss of polarization	Partitioning defective protein 3 (PARD3) is a part of Par complex built of atypical Protein Kinase C (aPKC)/Bazooka (Baz, PARD3)/Par-6. The Par complex determines cell polarity and asymmetric cell division. Opposite localization of Par complex and MARK2 defines the apicobasal axis	[46, 266]
	Autophagy pathways	↓	The autophagy pathway is a conserved cellular process of degradation of intracellular components that include soluble or aggregated proteins, organelles, macromolecular complexes, and foreign bodies. The formation of an autophagosome that ultimately fuses with a lysosome is driven by the cooperation of multiple factors	[267]
	Notch	↑	Notch signaling is a conserved pathway of cell–cell communication. The Notch receptor is localized on the signal-receiving cell, while ligands are located on the neighboring signal-sending cell. The effect of Notch signaling depends on the cellular context and can influence differentiation, proliferation and apoptotic cell fates	[268, 269]
	p38γ/Carm1	Mislocalization	Mitogen-activated protein kinase (MAPK) p38γ regulates SC fate through phosphorylation of Carm1, which further controls epigenetic induction of Myf5 expression during asymmetric SC division	[9]
	FGF2	↑	Fibroblast growth factor 2 (FGF2) is one of the FGFs that regulate SC function via activation of ERK MAPK, p38 MAPKs, PI3 kinase, PLCg and STATs. SCs express FGR receptors to detect FGF2 produced by myofibers, fibroblasts and satellite cells	[270]