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Rawls, A.; Diviak, B.K.; Smith, C.I.; Severson, G.W.; Acosta, S.A.; Wilson-Rawls, J. Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies. Encyclopedia. Available online: https://encyclopedia.pub/entry/52847 (accessed on 08 July 2024).
Rawls A, Diviak BK, Smith CI, Severson GW, Acosta SA, Wilson-Rawls J. Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies. Encyclopedia. Available at: https://encyclopedia.pub/entry/52847. Accessed July 08, 2024.
Rawls, Alan, Bridget K. Diviak, Cameron I. Smith, Grant W. Severson, Sofia A. Acosta, Jeanne Wilson-Rawls. "Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies" Encyclopedia, https://encyclopedia.pub/entry/52847 (accessed July 08, 2024).
Rawls, A., Diviak, B.K., Smith, C.I., Severson, G.W., Acosta, S.A., & Wilson-Rawls, J. (2023, December 18). Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies. In Encyclopedia. https://encyclopedia.pub/entry/52847
Rawls, Alan, et al. "Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies." Encyclopedia. Web. 18 December, 2023.
Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies
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This entry is adapted from the peer-reviewed paper 10.3390/biom13101536

Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutations. A common feature of the pathophysiology of muscular dystrophies is chronic inflammation associated with the replacement of muscle mass with fibrotic scarring. With the progression of these disorders, many patients suffer cardiomyopathies with fibrosis of the cardiac tissue. Anti-inflammatory glucocorticoids represent the standard of care for Duchenne muscular dystrophy, the most common muscular dystrophy worldwide; however, long-term exposure to glucocorticoids results in highly adverse side effects, limiting their use. Thus, it is important to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair.

muscular dystrophy dystrophin dysferlin Emery-Dreifuss dystroglycan LAMA2 FSHD

1. Introduction

Muscular dystrophies (MDs) are genetic degenerative neuromuscular diseases characterized by progressive muscle weakness that results in significant morbidity. To date, mutations in 57 genes have been identified that cause nine specific classes of muscular dystrophy [1]. Dystrophies are classified based on the specific gene involved and clinical features such as muscles affected, rate of disease progression, histopathology, and age of diagnosis. Inflammation is a common factor in the pathogenesis and progression of many types of MD. Chronic inflammation exacerbates muscle damage, induces fibrotic deposition and fatty replacement of myofibers, and impedes the regenerative process of skeletal muscle.

2. Duchenne and Becker Muscular Dystrophy

Duchenne muscular dystrophy (DMD), the most common and severe form of MD, is caused by mutations in the dystrophin (DMD) gene (Figure 1). This gene is located on the X chromosome [2], and DMD affects 1 in 3600 males born [3]. Clinically, DMD is characterized by muscle weakness and wasting during early childhood, with symptoms appearing by age 3. Initially, these patients have difficulty or pain with movement, frequent falls, a waddling gait, and delayed growth [4]. There is a loss of ambulation in childhood to early teens and death in early adulthood [5][6]. DMD patients also suffer significant cardiac complications; approximately 90% will progress to dilated cardiomyopathy marked by inflammatory cell infiltration, fibrosis, and myocardial cell death, leading to early mortality [7][8]. In contrast, Becker MD (BMD), the second most common form of muscular dystrophy, also caused by mutations in DMD, is found in 1.5–3.6/100,000 males globally. BMD is a milder disease, and patients typically are identified at 11–25 years of age; however, they may have much later ages of onset. BMD patients develop progressive weakness in the muscles of the hips, thighs, pelvis, and shoulders and generally have a nearly normal lifespan unless they experience cardiac failure [9].
Biomolecules 13 01536 g001
Figure 1. Schematic of the etiology of DMD/BMD, FSHD, and EDMD.
DMD is the largest gene in the human genome; it has 79 exons, and the full-length transcripts include unique tissue-specific first exons [10][11]. The dystrophin protein is 427 kDa in size, it consists of four domains; at the N-terminus, there is an actin-binding domain, which is followed by a central rod domain consisting of 24 spectrin-like repeats. Within the rod domain are four hinge regions at the N- and C- termini of the rod. The fourth hinge region is followed by the cysteine-rich domain that contains a dystroglycan binding site. At the C-terminus of dystrophin, there are α-syntrophin and dystrobrevin binding sites [12][13]. Dystrophin is part of a large multiprotein complex that acts to stabilize the myofiber membrane during muscle contraction to prevent contraction-induced damage [12][13]. The dystrophin–glycoprotein complex (DGC) includes the cytoplasmic proteins dystrobrevin and syntrophins, sarcolemmal transmembrane proteins β-dystroglycan, sarcoglycans, sarcospan, and an extracellular protein α-dystroglycan [13]. 
Loss of membrane integrity and stability in skeletal and cardiac muscle due to a lack of dystrophin underlies DMD pathology (Figure 1) [12][13][14]. There are thousands of mutations that are known to cause DMD/BMD. In DMD, 60–70% of the mutations are large deletions that span one or more exons, whereas approximately 26% are point mutations that result in frameshifts or premature termination [13]. The milder disease course and later onset of BMD are the result of mutations that maintain the reading frame while deleting exons in the midportion of the rod domain, resulting in a shorter but functional dystrophin protein [9][14].
Inflammation is necessary for the normal skeletal muscle repair process, but muscle damage in DMD/BMD results in a chronic inflammatory environment. In skeletal and cardiac muscle, functional muscle loss, including diaphragmatic weakness and respiratory insufficiency, is linked to fibrosis that is caused by chronic inflammation [7][8][15]. As muscle wasting progressively increases over time, skeletal muscle is replaced by extracellular matrix (ECM), resulting in fibrosis that further hinders the ability of dystrophic muscle to generate the necessary force. A key factor controlling fibrosis is transforming growth factor β (TGF-β), which is stored in the ECM. It promotes the synthesis and remodeling of ECM proteins during muscle regeneration. In dystrophic muscle, TGF-β is activated chronically and induces the deposition of fibrotic proteins such as collagen to replace degenerated muscle. Reducing fibrosis has been explored as a treatment avenue for DMD. Potential targets include TGF-β and connective tissue growth factor (CTGF) [16]. Immunosuppression with glucocorticoids, such as deflazacort or prednisone, is the current guideline treatment for DMD symptoms. Glucocorticoids are effective in reducing symptoms and slowing disease progression but are associated with many adverse side effects, including uneven and excessive weight gain, loss of bone density, reduced stature, behavioral changes, and even muscular atrophy, which all negatively impact the quality of life for patients [17][18][19].

2.1. Inhibition of Inflammation and Fibrosis

Edasalonexent (CAT-1004, is a small molecule NF-κB inhibitor that combines structural elements of salicylic acid and docosahexenoic acid [20]. A phase 3 placebo-controlled clinical trial of this drug in DMD boys (aged 4–8 years) found it to be safe and tolerated, but functional data from the North Star Ambulatory Assessment (NSAA) criteria showed a nonsignificant trend of improvement in younger patients (<6 years) (NCT03703882) [1]. Edasalonexent may prolong ambulation and delay respiratory and cardiac problems when prescribed for very young patients [20]. Unfortunately, Catabasis Pharmaceuticals stopped development of the drug.
Vamorolone, or VBP15, is a 21-aminosteroid or lazaroid, which is a glucocorticoid steroid that has a delta 9,11 modification of the backbone [21]. Vamorolone stabilizes membranes by reducing lipid peroxidation and inhibiting NF-kB-mediated inflammation. Importantly, vamorolone limits adverse steroid side effects because it binds the glucocorticoid receptor without activating gene expression via the glucocorticoid response element (GRE) [22][23][24][25]. 
Pamrevlumab is a monoclonal antibody specific for CTGF, which regulates pro-fibrotic pathways and is upregulated in DMD patients along with TGF-β [16]. FibroGen assessed pamrevlumab (FG-3019) in two clinical trials in DMD patients, examining its effect on limb muscles and respiratory function. Their phase 3 trial on upper limb performance in non-ambulatory DMD patients found that while pamrevlumab was safe and tolerated, it did not meet its primary endpoint (NCT04371666), whereas the phase 2 trial on respiratory function is ongoing (NCT02606136).
In response to muscle injury, the urokinase-type plasminogen activator and its receptor (uPA/uPAR) form a complex that leads to ECM breakdown, the release of TGF-β, and subsequent macrophage invasion, all necessary processes in the course of normal muscle repair.
Since TGF-β has a multifactorial role in signaling during regeneration, therapeutic strategies focused on limiting fibrosis often target this protein. One such strategy is a monoclonal antibody that targets latent transforming growth factor beta binding protein 4 (LTBP4), a matrix-embedded protein that sequesters TGF-β in the ECM and modulates its availability. LTBP4 also binds other members of the TGF-β superfamily, including myostatin, which may aid its efficacy [26]. The antibody is directed against the hinge region of LTBP4; when bound, it maintains the protein in a closed conformation, securing TGF-β and reducing the amount that is freely acting in muscle. Treatment of mdx mice for 6 months resulted in increased fiber size and less fibrosis, and there was a synergistic effect when combined with corticosteroids [26]. This preclinical study is encouraging for DMD patients, most of whom are treated with corticosteroids.

2.2. Calcium Homeostasis

Disruption of Ca2+ homeostasis in muscular dystrophy has been identified as a key contributor to skeletal myofiber and myocardial cell death [27][28][29]. Elevated cytosolic Ca2+ activates calcium-sensitive proteases, calpain and phospholipase A2, in myofibers, resulting in proteolysis and membrane damage. Though initially attributed to Ca2+ influx through microtears of the sarcolemma, it is clear that increased Ca2+ in the cytosol is caused by activation of channels in the membrane of the sarcoplasmic reticulum (SR), such as the ryanodine receptors (RyR1 and RyR2) and the sarcolemma, such as the transient receptor potential canonical channels (TRPC), voltage-gated Na+ channels (Nav1.4 and Nav1.5), and ionotropic purinoreceptors (P2 × 7). Further, in DMD, the reduced activity of the SERCA1 and SERCA2 channels that mediate Ca2+ uptake in the SR and the mitochondrial Ca2+ uniporter (MCU) also contributes to the loss of calcium homeostasis [30][31].
It has been hypothesized that the DGC serves as a scaffold for the assembly of the channels and facilitates the activation of mechanosensitive channels. Ion channels that promote Ca2+ influx through the sarcolemma cluster with the DGC by direct interactions with α-syntrophins [32]. In the absence of dystrophin, the integrity of many channels is disrupted, including TRPCs, store-operated Ca2+ entry (SOCE) channels, and voltage-gated Na+ channels, leading to an excessive influx of Ca2+ from the environment. Dystrophic muscle in mice, rats, and DMD patients overexpress TRPC1, TRPC3, and TRPC6, further increasing the Ca2+ influx into the muscle [33][34]. The activity of TRPC3 and TRPC6 is increased by phosphorylation by Ca2+ calmodulin-dependent kinase (CaMKII) and ERK1/2 and reduced N-linked glycosylation [35][36][37]. The importance of TRPC6 in DMD fibrosis and muscle weakening was demonstrated by treating Mdx/Utrn−/− mice, a severe model of DMD, orally with the TRPC6 antagonist BI 749327 [38]. Reduced TRPC6 activity in the double knock-out mice resulted in an extended lifespan, increased muscle and heart function, and reduced fibrosis in the gastrocnemius, diaphragm, and ventricle, as compared to untreated controls. Similar anti-fibrotic outcomes have been observed in mice for cardiac and renal disease [39]. 
Ryanodine receptors (RyR1-3) are a family of homotetrameric proteins located in the SR that release intracellular Ca2+ stores into the cytoplasm in response to membrane depolarization. It has been proposed that Ca2+ leakage into the cytosol through RyRs is due to the depletion of the co-factor calstabin-1 [40].
The level of cytosolic Ca2+ is affected by channels that pump Ca2+ back into organelles, including the SR and mitochondria. Perhaps the most important among these is the SR Ca2+ ATPase family (SERCA1 and 2), which can remove >70% of the Ca2+ from the muscle cytosol during muscle fiber relaxation [41]. In mouse MD models, SERCA activity is decreased due to the upregulation of an inhibitor, sarcolipin. Consistent with this, overexpression of a SERCA1 transgene or the knockdown of sarcolipin rescued the dystrophic tissue pathology in skeletal muscle and reduced myocardial fibrosis in mdx and Dmd/Utrn−/− mice [31][42][43].
The abnormally high intracellular Ca2+ concentrations and oxidative stress in the muscle of DMD patients lead to calcium overload of the mitochondria [44] and the opening of the mitochondrial permeability transition pore (MPTP). The open MPTP releases Ca2+ and ROS into the cytosol and increases oxidative stress and inflammation [45].
Alisporivir, also known as Debio-025, is a non-immunosuppressive analog of cyclosporin A (CsA) that inhibits the opening of the MPTP. This occurs by targeting cyclophilin D, one of the two proteins that make up MPTP [45][46]. Alisporivir was found to be effective in muscular dystrophy in mdx and δ-sarcoglycan−/− mice [47][48]. This drug is more effective than prednisone in decreasing muscle fibrosis and infiltration of macrophages and improving muscle regeneration in mdx mice [49]. 

2.3. Inhibition of Oxidative Stress

Oxidative stress causes dystrophic pathology by damaging tissue and interfering with repair mechanisms. High levels of reactive oxygen species (ROS) in tissues and cells damage proteins and DNA, induce lipid peroxidation reactions, and activate NF-κB, perpetuating the inflammatory state [50]. ROS levels are elevated in dystrophic muscle due to constant neutrophil invasion, increased activity of NADPH oxidase, and dissociation of nitric oxide synthase from the broken dystroglycan complex. Mitochondria also serve as a tightly regulated source of ROS but are dysfunctional in DMD due to the elevated Ca2+ levels due to the damaged sarcolemma.
Idebenone is a benzoquinone analog to coenzyme Q10 (CoQ10), which has a similar redox potential as CoQ10, meaning it can scavenge ROS in cells and tissues. It also increases ATP production, which is necessary for mitochondrial function, reduces free radicals, and inhibits lipid peroxidation, thus protecting membranes and mitochondria from oxidative damage. In a randomized controlled trial in DMD boys, idebenone demonstrated a trend of improved cardiovascular and respiratory function, but it was not significant [51]. 
MSS51 is a mitochondria-associated protein specific to skeletal muscle whose expression is decreased when myostatin is inhibited, suggesting a role in myostatin signaling. Mss51−/− mice were resistant to diet-induced weight gain and showed increased glycolysis, β-oxidation, and oxidative phosphorylation, indicating MSS51 has a role in the regulation of skeletal muscle mitochondrial respiration and glucose and fatty acid metabolism [52]. When Mss51 was knocked out in mdx mice, they demonstrated larger myofibers, less fibrosis, and greater mitochondrial respiration. These mice showed improvement in running endurance but not in grip strength [52]. 

3. Emery–Dreifuss Muscular Dystrophy (EDMD)

Emery–Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder characterized by a combination of skeletal muscle weakness, joint contractures, and cardiac abnormalities [53]. EDMD is rare; it has a prevalence estimated at 3 to 4 cases per million. Falling under the spectrum of laminopathies, EDMD is caused by mutations in at least 10 genes encoding nuclear envelope proteins. The most common types are caused by mutations in emerin (EMD) and lamin A (LMNA) [53][54][55]. EMD has an X-linked recessive inheritance [55], it encodes emerin, a nuclear membrane protein found at the interface of the nucleus with the cytoplasm. LMNA is inherited in an autosomal dominant fashion, and it codes for lamin A and C, which are type V intermediate filaments. The lamins polymerize under the inner nuclear membrane to form the nuclear lamina [56][57].
EDMD patients have diverse clinical presentations, making it challenging to diagnose and manage [53][55][58]. Patients with EDMD have three main sets of symptoms, which consist of early contractures, progressive muscle weakness and atrophy, and cardiac abnormalities. Joint contractures are a hallmark symptom of EDMD, causing multi-joint stiffness, reduced mobility, and functional impairment, most often involving the neck, elbows, and heel. Spinal rigidity may also affect posture, flexibility, and swallowing [53][55]. Progressive muscle weakness and wasting primarily affect the scapulo-humero-peroneal muscles in children, which impairs mobility and strength [53].
In the nucleus, emerin binds to lamin A, actin, and nuclear myosin, and as a complex, it regulates chromatin dynamics, acts as a mechanosensor for the nucleus, and participates in the regulation of gene expression [59][60][61][62]. EDMD pathophysiology involves disruptions in the nuclear envelope, resulting in loss of nuclear membrane integrity, heterochromatin decondensation, nucleoplasm leakage, chromatin detachment from the nuclear lamina, pseudoinclusions, and nuclear fragmentation (Figure 1) [53]. These defects contribute to cellular dysfunction, especially in tissues like cardiac and skeletal muscles that undergo mechanical stress [55]. Histologically, the heart demonstrates myocardial fibrosis and fibrolipomatosis, and skeletal muscle has dystrophic changes, including variation in fiber size, increased number of myofibers with centrally localized nuclei, increased endomysial connective tissue, and the presence of necrotic fibers [55].

EDMD Treatment

EDMD is a challenging and genetically complex disorder, necessitating ongoing research to advance our understanding of the disease and develop effective therapeutic strategies [55][63]. Timely cardiac interventions, regular monitoring, and supportive care are also essential in improving the prognosis and quality of life for individuals with EDMD [53]. Currently, the therapeutic approaches for EDMD patients are limited to the alleviation of symptoms, slowing disease progression, and improving the overall quality of life [53]. Much like DMD and BMD patients, glucocorticoids are prescribed to limit inflammation [54]. Due to side effects associated with long-term use of glucocorticoids, anti-inflammatory and anti-fibrotic agents are being examined in mouse models for EDMD.

4. Facioscapulohumeral Muscular Dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is the third most prevalent type of MD, following myotonic dystrophy type 1 and DMD, estimated to affect 1 in 15,000 to 1 in 20,000 people [64]. FSHD is inherited in an autosomal dominant manner; however, approximately 30% are de novo cases. Additionally, there is a high frequency of somatic mosaicism [65]. FSHD typically presents with weakness in one or more of these facial muscles, the stabilizers of the scapula, or the dorsiflexors of the foot. Muscle weakness is slowly progressive and, with time, can involve the axial and respiratory muscles and those of the lower limbs [66].
Histopathological studies of human FSHD biopsies have shown that there are regenerating myofibers of varying sizes; inflammation and fibrosis that is both endomysial and perivascular were prominent, and there was significant fat replacement of the muscle fibers [67]. A two-year prospective study of FSHD patients found that inflammation was mild in the early stages, but its presence was related to an increased rate of muscle degradation and fat infiltration [68]. When examining RNAseq and microarray data from FSHD biopsies, it was noted that inflammatory genes have increased levels of expression [69]. FSHD myoblasts have increased sensitivity to oxidative stress and are prone to apoptosis because double homeobox protein 4 (DUX4) affects mitochondrial function. 
DUX4 is the gene affected in FSHD patients [70][71]. DUX4 is expressed in pre-implantation embryos, and Dux binding sites are found in the control regions of genes involved in early genome activation [69][70]. DUX4 is important in early embryos for embryonic genome activation (EGA). DUX4 triggers this process and subsequently becomes inactive [72][73][74][75][76]. Postnatally, DUX4 is expressed at low levels in the testis and the thymus. Ectopic expression in skeletal muscle postnatally results in FSHD [77][78][79]. The human DUX4 gene is located on chromosome 4 in a region known as D4Z4, which consists of 11 to more than 100 repeated 3300 DNA base pair segments. Each of the repeated segments in the D4Z4 region contains a copy of the DUX4 gene; the copy closest to the end of chromosome 4 is called DUX4, while the other copies are referred to as “DUX4-like” or DUX4L [80][81]

5. Limb-Girdle Muscular Dystrophy

Limb-girdle muscular dystrophy (LGMD) is the largest group of muscular dystrophies. They were originally defined by the progressive wasting of skeletal muscles of the pelvic and pectoral girdles. These dystrophies show significant variation in the onset of the disease, degree of wasting and inclusion of cardiomyopathy, cardiac arrhythmias, and respiratory failure [82]. There are 24 genetic subtypes based on disease phenotype and mutations: (i) sarcoglycan complex (LGMD2C-F); (ii) glycosylation/α-dystroglycan complex (LGMD2I, LGMD2K, LGMD2M, LGMD2N, LGMD2O, LGMD2P, LGMD2S, LGMD2T, LGMD2U, LGMD2Z); (iii) sarcomeric proteins (LGMD1A, LGMD1D, LGMD1E, LGMD2A, LGMD2G, LGMD2J, LGMD2Q, and LGMD2R); (iv) signal transduction (LGMD1C, LGMD2P, LGMD2W); and (v) membrane trafficking and repair (LGMD1C, LGMD1F, LGMD2B, LGMD2L). These disorders are relatively rare compared to DMD, with individual estimated prevalences of 0.01–0.60 cases per 100,000 persons [83]. The rarity of these disorders limits the ability to carry out clinical trials to examine the effectiveness of therapeutic strategies discovered in mice [84]. 

5.1. Sarcoglycanopathy

Sarcoglycan consists of four subunits, α, β, γ, and δ, that form an integral membrane protein complex that is a subunit of the DGC in skeletal muscle. This protein complex is essential for the structural stability of the sarcolemma in both skeletal and cardiac muscle (Figure 2). Genetic mutations of any sarcoglycan subunit are inherited in an autosomal dominant fashion and result in sarcoglycanopathy, which has a similar phenotype to DMD. In sarcoglycanopathy, or LGMD2, the average age at onset of muscle weakness is 6–8 years, with loss of ambulation at 12–16 years old. Similar to DMD, cardiomyopathy and respiratory complications following the loss of ambulation are commonly observed [82][85][86]. At the tissue level, muscle weakness is associated with chronic inflammation and the replacement of muscle fibers with fat depositions and fibrosis [87].
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Figure 2. Schematic of the etiology of subgroups of LGMDs.

5.2. Dystroglycanopathies

Dystroglycanopathies are autosomal recessive dystrophic disorders with variability in the age of onset and degree of muscle wasting. α- and β-dystroglycan form an integral membrane protein complex that links the basement membrane to the cytoplasmic dystrophin protein. α-dystroglycan binds to ECM and synaptic proteins and is dependent on heavy glycosylation [88]. Dystroglycanopathies are primarily linked mutations in glycosyltransferases that target α-dystroglycan, including fukutin-related protein (FKRP/LGMD2I) [89], fukutin (FKTN/LGMD2M), -like-acetylglucosaminyl transferase (LARGE), protein-O-mannosyltransferase 1 (POMT1/LGMD2K), protein-O-mannosyl transferase 2 (POMT2/LGMD2N), protein-O-mannose-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1/LGMD2O), dolichyl-phosphate mannosyltransferase polypeptide 3 (DPM3), and isoprenoid synthase domain containing (ISPD/LGMD2U) [90][91][92][93][94][95]. A rare subset of dystroglycanopathies includes mutations in the dystroglycan gene (DAG1). These mutations cluster in the N-terminal domain of α-dystroglycan or in the domains that stabilize the α/β-dystroglycan interface [96]. Though these milder forms of muscular dystrophy are classified as LGMD based on their progressive muscle wasting in the extremities, more severe congenital muscular dystrophies are associated with mutations in glycosyltransferases targeting α-dystroglycan that result in a non-progressive muscle weakness that is observed at birth. Most notable among these are Walker–Warburg (WWS) and muscle eye brain syndromes (MEB), which present with an earlier onset of muscle weakness and include complex eye and brain disorders [97][98].
The most common form of dystroglycanopathy, LGMD2I, is caused by mutations in FKRP; it occurs at a frequency of 1 in 250,000 in the U.S. The use of corticosteroids to reduce fibrosis and muscle loss has shown promise with LGMD2I. Mice that recapitulate the LGMD2I phenotype through mutation of FKRP [95] have reduced pathology and muscle degeneration when treated with prednisolone, though it did not improve muscle strength. However, in combination with the bisphosphonate, alendronate, which is normally administered to limit osteoporosis, the level of muscle damage was lessened, and muscle function was improved [94]. Under both conditions, the level of glycosylated α-dystroglycan increased, suggesting a mechanism other than immunosuppression for injury reduction. 

6. Congenital Muscular Dystrophy

6.1. LAMA2-Related Muscular Dystrophy

MDC1A patients display hypotonia and muscle wasting at birth and with progressive spinal deformities and contractures of the major limb joints in early childhood [99][100]. These patients can suffer from neuropathies under the age of 1 and can experience cerebral atrophy and seizures in older individuals [101][102][103]. In severe cases, the loss of muscle strength complicates swallowing and breathing, and death due to respiratory insufficiency can occur in the first decade, though their usual life expectancy is the thirties [104][105].
Inflammation and fibrosis play prominent roles in the early onset of muscle weakness in MDC1A [106]. Individuals experience a burst of inflammation in their skeletal muscle as early as a couple of months after birth. This leads to the expansion of the interstitial ECM between myofibers, resulting in fibrosis. Unlike DMD, where fibrosis builds over time with repeated rounds of muscle breakdown and repair, fibrosis in MDC1A appears early and is maintained [106].
Fibrosis in MDC1A muscle has been linked to the TGF-β and renin-angiotensin signaling pathways. TGF-β is a primary regulator of fibrotic deposition via its roles in promoting the expression of ECM proteins and the conversion of satellite cells to a fibroblastic lineage [16][107]. 
Therapeutic strategies designed to reduce fibrosis in MDC1A patients have largely focused on reducing TGF-β levels. One approach that has shown promise is the AT1R blocker losartan. Though initially approved by the FDA to control hypertension, it effectively reduced fibrosis in the dyW/dyW and dy2J/dy2J by disruption of Ang II signaling through AT1R, which inhibits the conversion of TGF-β to its active form [108][109][110][111]. Losartan treatment also decreased ERK phosphorylation and fibrosis in dyW/dyW mice [108].
The FDA-approved serine/threonine kinase inhibitor vemurafenib effectively ameliorates fibrosis in dy3K/dy3K mice [112]. Treatment resulted in a reduction in TGF-β and mTORC1/p70S6K signaling. Much like losartan, vemurafenib was able to block the pro-fibrotic pathway but was unable to promote muscle repair. This raises concerns about its use as a solo therapy. 
In addition to blocking the TGF-β signaling pathway that directly induces fibrosis and inflammation, other research groups have explored the therapeutic benefits of blocking secondary events associated with muscle pathology in MDC1A patients and mouse models. Perhaps the most promise has been reported with omigapil, an inhibitor of the pro-apoptotic protein, Bax, and the GAPDH-Siah apoptosis cascade [113][114]
The pathology in Lama2-deficient mice appears to be exacerbated by the upregulation of lysosome-associated degradation pathways in the muscle [115][116]. Consistent with this, inhibition of the ubiquitin-proteasome system by treatment of dy3K/dy3K mice with MG-132 or bortezomib increased muscle strength and mobility and reduced muscle fibrosis while extending the mouse’s lifespan [115][117]. In wildtype mice, Lama2 acts as an inhibitor of autophagy through the inhibition of the class III PI3K Vps34. 

6.2. Collagen VI-Related Dystrophies

ColVI is a beaded fibril consisting of three chains encoded by COL6A1, COL6A2, and COL6A3. The ColVI collagen fibers form a mesh-like network associated with the ECM of basement membranes, where it can modify the nature of the structure based on binding to glycoproteins, proteoglycans, and glycosaminoglycans [118]. They serve important roles in protecting cells from compressive forces while facilitating the interaction between cells and ECM proteins. Further, ColVI participates in the regulation of autophagy through direct interaction with integral membrane proteins on adjacent cells (β1 integrin, TEM8, and VEGFR2) [119][120][121].
Mutations in COL6A1, COL6A2, and COL6A3 lead to a spectrum of congenital muscular dystrophies that range from UCMD at the severe end of the spectrum to Bethlem myopathy at the mild end [118]. UCMD patients experience congenital hypotonia and contractures in joints of the extremities.
The histopathology associated with muscle weakness in ColVI-related dystrophies includes muscle fibers of various sizes and a significant increase in interstitial fibrosis [122]. As with MDC1A, fibrosis accumulation is immediate and does not build with time, as seen with DMD. Using Col61A-deficient mice as a model, fibrosis was found to be related to overactivation of mesenchymal stem cells that have been converted to the fibroblast lineage [122].

7. Conclusions

Advances in genetic, genomic, and proteomic technologies have resulted in an acceleration in the unraveling of the molecular mechanisms underlying the histopathology of more than 50 types of muscular dystrophy and opened the door to an exploration of alternative therapeutic approaches to glucocorticoid suppression of fibrosis, fat accumulation, and chronic inflammation associated with most muscular dystrophies. Strategies with broad promise are those that reduce proinflammatory NF-κB and TNF-α signaling. Studies in mouse models have shown success in ameliorating the pathology upstream of their expression through antioxidants (e.g., COX enzyme inhibitor) [123], suppression of the inflammasome (e.g., P2X7 antagonists) [124] or directly through the inhibition of NF-κB activity (e.g., vamorolone) [125]. Alternatively, inhibition of the Akt/mTOR signaling pathway by rapamycin suppresses the immune response to injury by reducing the proliferation of immune cells [126]. This has shown potential for ameliorating fibrosis in Lmna- and Ftkn-deficient mice [98][127][128][129]. Recent reports predict that direct suppression of fibrotic deposition in fibroblasts at the site of injury by disrupting uPA/uPAR signaling via Serp-1 represents a strategy downstream of chronic inflammation to reduce fibrosis [130][131][132].

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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Alan Rawls
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Bridget K. Diviak
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Cameron I. Smith
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Grant W. Severson
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Sofia A. Acosta
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Jeanne Wilson-Rawls
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Update Date: 18 Dec 2023
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