Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Maria Pennuto
 -- 2550 2022-07-26 22:51:44 |
2 Reference format revised.
Lindsay Dong
-8 word(s) 2542 2022-07-27 04:55:33 | |
3 Reference format revised.
Lindsay Dong
Meta information modification 2542 2022-07-28 08:14:58 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Marchioretti, C.;  Zuccaro, E.;  Pandey, U.B.;  Rosati, J.;  Basso, M.;  Pennuto, M. Skeletal Muscle Pathogenesis in Polyglutamine Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/25548 (accessed on 22 July 2024).
Marchioretti C,  Zuccaro E,  Pandey UB,  Rosati J,  Basso M,  Pennuto M. Skeletal Muscle Pathogenesis in Polyglutamine Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/25548. Accessed July 22, 2024.
Marchioretti, Caterina, Emanuela Zuccaro, Udai Bhan Pandey, Jessica Rosati, Manuela Basso, Maria Pennuto. "Skeletal Muscle Pathogenesis in Polyglutamine Diseases" Encyclopedia, https://encyclopedia.pub/entry/25548 (accessed July 22, 2024).
Marchioretti, C.,  Zuccaro, E.,  Pandey, U.B.,  Rosati, J.,  Basso, M., & Pennuto, M. (2022, July 26). Skeletal Muscle Pathogenesis in Polyglutamine Diseases. In Encyclopedia. https://encyclopedia.pub/entry/25548
Marchioretti, Caterina, et al. "Skeletal Muscle Pathogenesis in Polyglutamine Diseases." Encyclopedia. Web. 26 July, 2022.
Skeletal Muscle Pathogenesis in Polyglutamine Diseases
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cells11132105

Polyglutamine diseases are characterized by selective dysfunction and degeneration of specific types of neurons in the central nervous system. In addition, nonneuronal cells can also be affected as a consequence of primary degeneration or due to neuronal dysfunction. Skeletal muscle is a primary site of toxicity of polyglutamine-expanded androgen receptor, but it is also affected in other polyglutamine diseases, more likely due to neuronal dysfunction and death. Nonetheless, pathological processes occurring in skeletal muscle atrophy impact the entire body metabolism, thus actively contributing to the inexorable progression towards the late and final stages of disease. 

Huntington’s disease spinal and bulbar muscular atrophy spinocerebellar ataxia skeletal muscle atrophy polyglutamine diseases

1. Introduction

Polyglutamine diseases are a family of nine neurodegenerative diseases that includes spinal and bulbar muscular atrophy (SBMA); Huntington’s disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, and 17 [1][2]. Polyglutamine diseases are caused by expansions of the cytosine-adenine-guanine (CAG) trinucleotide repeat in the exons of specific genes. These genes code for unrelated proteins, that is, androgen receptor (AR), huntingtin (HTT), atrophin-1, ataxin-1, ataxin-2, ataxin-3, α1a-subunit of the P/Q voltage-dependent calcium channel (CACNA1A), ataxin-7, and the TATA-box binding protein (TBP). CAG expansions result in the production of proteins with aberrantly expanded polyglutamine tracts. All polyglutamine diseases are autosomal dominant, except SBMA, which is X-linked. Polyglutamine diseases belong to the family of brain misfolding diseases, which are a large group of neurodegenerative disorders that also includes Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and many others [3]. Brain misfolding diseases represent a major health burden for the entire world with an estimated number of more than 30 million patients in the next 50 years [4][5]. Brain misfolding diseases share several commonalities, such as being late-onset and progressive diseases. Symptoms typically manifest around the third to fifth decade of life, except for the juvenile forms observed in patients with very long repeats [6][7]. Another key feature is neuronal loss, and neurons seem to be extremely vulnerable in these conditions despite the fact that, very often, the disease-related proteins have ubiquitous expression and housekeeping functions in the cells [8][9]. One such example is TBP, which is the universal basal transcription factor expressed in all cell types and controlling the expression of nearly all genes.

2. Clinical Presentation and Disease Pathogenesis of Polyglutamine Diseases

Polyglutamine expansions cause neurodegeneration mainly through toxic gain-of-function mechanisms. It is worth noting that patients may also show symptoms that partially overlap with loss-of-function mutations of the polyglutamine protein-encoding genes. This scenario is particularly evident in SBMA, thus indicating that loss-of-function mechanisms also contribute at least in part to disease pathogenesis.

HD is characterized by the dysfunction and loss of cortico-striatal neurons [10], with clinical manifestations spanning from cognitive to psychiatric and motor (chorea) symptoms. Disease progression is associated with body weight loss and progressive skeletal muscle weakness, wasting, and atrophy. HTT is widely expressed in the body, including skeletal muscle. At the subcellular level, HTT localizes to the nucleus, cytosol, endoplasmic reticulum, Golgi apparatus, and mitochondria. In the neurons, HTT has also been detected in the synaptic compartment. HTT has been implicated in several processes, from the synthesis of brain-derived neurotrophic factor (BDNF) to vesicular trafficking, ciliogenesis, and others.

SBMA is the only polyglutamine disease that is X-linked and male-specific [11][12]. The reason for the sex bias of SBMA is that males have higher circulating androgen levels than females, and polyglutamine-expanded AR requires androgen binding to exert most of its neurotoxic effects. SBMA is characterized by the loss of lower motor neurons and primary involvement of skeletal muscle.

DRPLA is characterized by the degeneration of neurons in the dentate nucleus of the cerebellum and pallidum [13]. Patients present with cerebellar ataxia, chorea, epilepsy, and dementia. Atrophin-1 localizes mainly to the cytosol, but it is also present in the nucleus and is involved in protein trafficking and degradation.
Polyglutamine ataxias are characterized by the primary loss of Purkinje cells [14]. Particularly interesting is the case of SCA17, as TBP regulates the expression of genes transcribed by the three eukaryotic RNA polymerases in the nucleus.
Within the family of polyglutamine disease-causing proteins, AR and TBP are the most well-known proteins in terms of structure and function; they are both transcription factors. TBP is composed of two domains, the amino-terminal domain that is intrinsically disordered, and the carboxy-terminal domain that is highly conserved and ordered into beta-sheets motifs. TBP binds to TATA-box or is recruited by basal transcription factors to the TATA-less promoters and plays a fundamental role in the process of initiation of transcription. AR is composed of three domains. Similar to TBP, AR has an intrinsically disordered amino-terminal domain, a DNA-binding domain (two zinc fingers,) and the ligand-binding domain that forms 12 alpha-helices and two beta-sheets. How polyglutamine expansions affect TBP and AR function is not known.

3. Muscle Pathology in Polyglutamine Disease Patients

Polyglutamine-expanded proteins cause damage to several tissues through cell-autonomous and noncell-autonomous mechanisms [15][16]. Peripheral symptoms are important components of HD manifestations, highlighting the relevance of peripheral toxicity of mutant HTT in the onset and progression of disease [17]. It is interesting to note that CAG expansions in HD patients were reported to be higher in skeletal muscle compared to lymphocytes, which may suggest why skeletal muscles are more prone to or are a primary site of the disease [18]. HD patients undergo progressive severe body mass loss, which is mainly due to skeletal muscle wasting [19]. HD patients show skeletal muscle weakness and signs of peripheral motor pathology, such as defects in eye movements and swallowing, gait abnormalities, reduced lower limb muscle strength, and dysarthria [20][21][22]. Changes in body composition and muscle wasting were not detected in a cohort of HD patients with early-to-moderate symptoms [23]. However, reduction of lean and fat body mass was reported in other HD patient cohorts as an early phenomenon [24].

SBMA represents the only neuromuscular disease within the family of polyglutamine diseases with selective degeneration of lower motor neurons resulting in skeletal muscle atrophy [25]. SBMA patients show fatigue, muscle weakness and atrophy, fasciculations, and reduced contractility [26]. SBMA muscles are characterized by neurogenic signs, such as fiber atrophy and fiber-type grouping, and myopathic changes, such as the presence of centronucleated fibers and fiber splitting and degeneration [27]. SBMA patients have very high levels of serum creatine kinase, much more than observed in patients suffering from neurogenic atrophy [28], even years before the appearance of symptoms [29]. Interestingly, in SBMA patients, the severity of peripheral symptoms directly correlates with the length of the pathogenic CAG repeat [30][31]. Although high androgen levels are responsible for disease manifestations in SBMA, an intriguing observation was that muscle strength positively correlates with testosterone levels in patients [32]. Thus, in SBMA patients, muscle atrophy is likely to result from the combination of toxic gain-of-function and loss-of-function mechanisms.

4. Skeletal Muscle Pathology Is Recapitulated in Mouse Models of Polyglutamine Diseases

Many of the peripheral symptoms observed in patients suffering from polyglutamine diseases are well recapitulated in R6/2 mice, which express a portion of the human HD gene under human gene promoter elements (1 kb of 5 UTR sequence and exon 1 together with ~120 CAG repeats) and represent a valuable model of HD, and knock-in mice expressing HTT-150Q [33][34], SCA17 [35], and SBMA [36][37][38]. HD mice develop diabetes and metabolic syndrome, motor dysfunction, mitochondrial abnormalities, skeletal muscle weakness and wasting, and body weight loss [39][40][41]. Some of these symptoms, namely glucose intolerance and insulin insensitivity, dyslipidemia, muscle wasting, and body weight loss, have been described also in knock-in and transgenic SBMA mice [42][43], as well as in knock-in mice with either pan- or muscle-specific expression of mutant TBP modeling juvenile forms of SCA17 [35]. HD R6/2 transgenic mice with a pathologically expanded CAG tract show motor abnormalities starting early and progressively enhancing in terms of severity and manifestations. Motor dysfunction is associated with muscle denervation, neuromuscular junction (NMJ) abnormalities, defects in muscle contraction and calcium dynamics, and loss of muscle regenerative capacity [39][44]. Different from SOD1-linked ALS, HD, SBMA, and SCA17 mice do not develop paralysis. This is consistent with a lack of structural denervation. Rather, polyglutamine disease models show mild-to-severe functional denervation, with severe structural abnormalities at the NMJ occurring at the late stage of disease and not associated with motor neuron loss, as reported in several SBMA mice [36][37]. Defects in neuromuscular transmission are associated with skeletal muscle hyperexcitability in knock-in and transgenic SBMA mice [45][46].
In the case of SBMA, the development of multiple animal models for conditional expression of polyglutamine-expanded AR has allowed establishing that skeletal muscle is a primary target of toxicity. Overexpression of polyglutamine-expanded AR in all tissues but skeletal muscle prevented the development of symptoms in transgenic mice, indicating that expression of the disease protein is necessary for triggering disease manifestations at least in mice [47]. Conversely, overexpression of non-expanded AR solely in skeletal muscle elicited a phenotype resembling SBMA, indicating that dysregulation of AR signaling is toxic to muscle [48].

5. Pathological Processes in the Skeletal Muscle in Polyglutamine Diseases

Aggregation and inclusion body formation A hallmark of neurodegenerative diseases is the deposition of mutant proteins into inclusion bodies, which sequester cellular proteins, such as components of the ubiquitin-proteasome system and autophagy degradation machineries causing alterations of the cellular proteome. Inclusion bodies are present in the central nervous system of HD patients and animal models of disease. Importantly, inclusion bodies have been detected not only in neurons but also in skeletal muscle fibers and other peripheral tissues of R6/2 mice and knock-in mice expressing HTT-150Q [33][49][50], as well as in primary myotubes derived from skeletal muscle biopsies of HD patients [51]. Similarly, inclusions have been detected in the skeletal muscle of mouse models of SBMA [36][38][52][53]. Inclusions positive for mutant HTT and AR are found in the cytosol and nucleus as a single structure in most cases, and their appearance correlates with the onset of muscle atrophy.
Mitochondrial pathology. Body weight and skeletal muscle function and homeostasis are tightly linked to mitochondrial function. HD muscles are characterized by mitochondrial dysfunction with defects in oxidative phosphorylation and ATP production in patients and mouse models [54][55][56]. These deficits are detected in presymptomatic patients, indicating that they occur early and are possibly causative of muscle atrophy and energy unbalance. The relevance of skeletal muscle in body homeostasis is underlined also by the observation that the R6/2 mice present with elevated energy expenditure, reduced body weight, and increased adiposity, all defects not due to reduced food intake [51]. HD myofibers show mitochondrial depolarization, reduced oxygen consumption, cytochrome c release, oxidative stress, and induction of apoptosis [51]. ATP production in skeletal muscle mitochondria is reduced not only in HD patients but also in DRPLA patients, indicating impaired energy metabolism [40]. Mitochondrial pathology is a key component of SBMA muscle pathology, as reported in many cellular and animal models of SBMA [42][57][58][59][60][61].
Altered muscle metabolism and fiber-type switch. Both SBMA [42][43] and HD [39][41][62][63] muscles undergo a glycolytic-to-oxidative metabolic switch associated with fast-to-slow fiber-type change. Loss of type IIb fibers and switch to type I fibers was also reported in a juvenile DRPLA patient [64]. The glycolytic-to-oxidative switch precedes signs of denervation and neuropathy in SBMA knock-in mice [42] and transgenic mice [36]. These metabolic alterations are associated with fiber-type changes, with progressive loss of type II glycolytic fibers and concomitant increase in type IIa and IIx fibers as the disease approaches advanced stages. Consistent with these metabolic alterations, SBMA muscle is characterized by an early down-regulation of expression of glycolytic genes and a concomitant up-regulation of oxidative genes, again long before the appearance of neurogenic signs of muscle pathology.
Activation of anabolic and catabolic pathways in the skeletal muscle of polyglutamine diseases. Skeletal muscle homeostasis is maintained by the balance between anabolic and catabolic pathways. Expression of polyglutamine-expanded AR and polyglutamine-expanded HTT results in increased protein synthesis and activation of protein kinase B (also known as Akt)/mechanistic target of rapamycin (mTOR) pathway in skeletal muscle [42][65]. Activation of these anabolic pathways likely occurs to compensate for increased energy demand. At the same time, activation of catabolic pathways leads to protein degradation via proteasome and autophagy. SBMA muscle is indeed characterized by the upregulation of expression of the atrogenes, genes that are induced upon muscle damage and atrophy and that are involved in protein degradation [66]. At the same time, genes involved in autophagy are upregulated, likely with the involvement of transcription factor EB (TFEB) [42], which is dysregulated in polyglutamine diseases [67]. Chronic activation of these pathways is associated with activation of caspases that result in cell death via apoptosis, inflammation, and atrophy [66].
Gene expression dysregulation. Polyglutamine expansions affect gene expression. Interestingly, gene expression changes are similar in the central nervous system and skeletal muscle of transgenic and knock-in HD mice [62]. Importantly, gene expression changes have been detected in skeletal muscle not only in HD mice but also in patients [41]. Among the genes dysregulated in HD and SBMA transgenic and knock-in mice, several genes code for proteins involved in skeletal muscle contractility and reactivation of expression of denervation markers associated with the loss of motor units [37][42][43][68][69]. Importantly, it was reported that HD muscles were characterized by early loss of expression of muscle chloride CIC-1 and potassium Kv3.4 channels, resulting in muscle hyperexcitability [70][71].

6. Modeling Skeletal Muscle in a Dish

With the exception of SBMA, analysis of skeletal muscle pathology in patients suffering from polyglutamine diseases is limited by the fact that muscle biopsies are not available. Due to the severity of these conditions, muscle biopsies are not routinely performed unless recommended by the physician. Muscle biopsies give the possibility to grow primary satellite cells that can be differentiated into myoblasts and myotubes for further analysis [72][73]. An alternative approach is represented by the use of induced pluripotent stem cells (iPSCs) derived from skin biopsies of patients and healthy controls. These cells can be differentiated into satellite cells [74][75], in two-dimensional (2D) cell cultures [76], and in three-dimensional (3D) human microphysiological systems that mimic the key structural and functional properties of skeletal muscle [77][78][79]. The iPSCs obtained from patients can be differentiated into several cell types, such as motor neurons, astrocytes, microglia, medium spiny neurons, neural precursors, and retinal photoreceptors [80][81][82][83][84][85][86]. SBMA, HD, and SCA iPSC-derived neural cells exhibit defects that recapitulate the principal pathological features observed in mouse models, suggesting that these cells are an extremely relevant model to study biochemical/molecular pathways and to screen drugs with beneficial effects. Polyglutamine iPSC-derived muscle cells will give researchers much information regarding the onset of disease, progression, and cell-autonomous mechanisms.

7. Conclusions

The relevance of skeletal muscle homeostasis in neurodegenerative diseases is underlined by the fact that this tissue is a valuable therapeutic target. Intervention to ameliorate skeletal muscle metabolism and reduce atrophy is effective in animal models of polyglutamine diseases. Pharmacologic inhibition of myostatin ameliorates muscle atrophy and body weight loss, indicating that it has beneficial effects on the phenotype of HD mice [87]. Ghrelin administration to HD mice ameliorates muscle atrophy and pathology, further supporting the idea that skeletal muscle is important in HD pathogenesis and is a key target tissue for therapy development [88]. Pharmacologic strategies to reduce polyglutamine-expanded AR expression in skeletal muscle ameliorates disease in knock-in SBMA mice [89]. Genetic and pharmacologic strategies to stimulate insulin-like growth factor 1 signaling ameliorate the phenotype of transgenic SBMA mice [90][91]. Moreover, treatment of SBMA mice with the beta-agonist, clenbuterol, attenuates symptoms [92], an approach that has benefits also in SBMA patients [93][94]. Therefore, strategies to delay or attenuate skeletal muscle westing and atrophy and improve metabolism may have beneficial effects on body metabolism and central nervous system function.

References

  1. Stoyas, C.A.; La Spada, A.R. The CAG-polyglutamine repeat diseases: A clinical, molecular, genetic, and pathophysiologic nosology. Handb. Clin. Neurol. 2018, 147, 143–170.
  2. Bunting, E.L.; Hamilton, J.; Tabrizi, S.J. Polyglutamine diseases. Curr. Opin. Neurobiol. 2022, 72, 39–47.
  3. Bertram, L.; Tanzi, R.E. The genetic epidemiology of neurodegenerative disease. J. Clin. Investig. 2005, 115, 1449–1457.
  4. GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health 2022, 7, e105–e125.
  5. GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1923–1994.
  6. Ghosh, R.; Tabrizi, S.J. Clinical Features of Huntington’s Disease. Adv. Exp. Med. Biol. 2018, 1049, 1–28.
  7. Mao, R.; Aylsworth, A.S.; Potter, N.; Wilson, W.G.; Breningstall, G.; Wick, M.J.; Babovic-Vuksanovic, D.; Nance, M.; Patterson, M.C.; Gomez, C.M.; et al. Childhood-onset ataxia: Testing for large CAG-repeats in SCA2 and SCA7. Am. J. Med. Genet. 2002, 110, 338–345.
  8. Roselli, F.; Caroni, P. From intrinsic firing properties to selective neuronal vulnerability in neurodegenerative diseases. Neuron 2015, 85, 901–910.
  9. Liu, Q.; Huang, S.; Yin, P.; Yang, S.; Zhang, J.; Jing, L.; Cheng, S.; Tang, B.; Li, X.J.; Pan, Y.; et al. Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17. Nat. Commun. 2020, 11, 1101.
  10. Saudou, F.; Humbert, S. The Biology of Huntingtin. Neuron 2016, 89, 910–926.
  11. Pennuto, M.; Rinaldi, C. From gene to therapy in spinal and bulbar muscular atrophy: Are we there yet? Mol. Cell Endocrinol. 2018, 465, 113–121.
  12. Arnold, F.J.; Merry, D.E. Molecular Mechanisms and Therapeutics for SBMA/Kennedy’s Disease. Neurotherapeutics 2019, 16, 928–947.
  13. Tsuji, S. Dentatorubral-pallidoluysian atrophy. Handb. Clin. Neurol. 2012, 103, 587–594.
  14. McIntosh, C.S.; Li, D.; Wilton, S.D.; Aung-Htut, M.T. Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies. Biomedicines 2021, 9, 1499.
  15. Sambataro, F.; Pennuto, M. Cell-autonomous and non-cell-autonomous toxicity in polyglutamine diseases. Prog. Neurobiol. 2012, 97, 152–172.
  16. Huang, S.; Zhu, S.; Li, X.J.; Li, S. The Expanding Clinical Universe of Polyglutamine Disease. Neuroscientist 2019, 25, 512–520.
  17. Carroll, J.B.; Bates, G.P.; Steffan, J.; Saft, C.; Tabrizi, S.J. Treating the whole body in Huntington’s disease. Lancet Neurol. 2015, 14, 1135–1142.
  18. Ansved, T.; Lundin, A.; Anvret, M. Larger CAG expansions in skeletal muscle compared with lymphocytes in Kennedy disease but not in Huntington disease. Neurology 1998, 51, 1442–1444.
  19. Costa de Miranda, R.; Di Lorenzo, N.; Andreoli, A.; Romano, L.; De Santis, G.L.; Gualtieri, P.; De Lorenzo, A. Body composition and bone mineral density in Huntington’s disease. Nutrition 2019, 59, 145–149.
  20. Djousse, L.; Knowlton, B.; Cupples, L.A.; Marder, K.; Shoulson, I.; Myers, R.H. Weight loss in early stage of Huntington’s disease. Neurology 2002, 59, 1325–1330.
  21. Hamilton, J.M.; Wolfson, T.; Peavy, G.M.; Jacobson, M.W.; Corey-Bloom, J.; Huntington Study, G. Rate and correlates of weight change in Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 2004, 75, 209–212.
  22. Busse, M.E.; Hughes, G.; Wiles, C.M.; Rosser, A.E. Use of hand-held dynamometry in the evaluation of lower limb muscle strength in people with Huntington’s disease. J. Neurol. 2008, 255, 1534–1540.
  23. Cubo, E.; Rivadeneyra, J.; Gil-Polo, C.; Armesto, D.; Mateos, A.; Mariscal-Perez, N. Body composition analysis as an indirect marker of skeletal muscle mass in Huntington’s disease. J. Neurol. Sci. 2015, 358, 335–338.
  24. Mielcarek, M. Huntington’s disease is a multi-system disorder. Rare Dis. 2015, 3, e1058464.
  25. Manzano, R.; Soraru, G.; Grunseich, C.; Fratta, P.; Zuccaro, E.; Pennuto, M.; Rinaldi, C. Beyond motor neurons: Expanding the clinical spectrum in Kennedy’s disease. J. Neurol. Neurosurg. Psychiatry 2018, 89, 808–812.
  26. Dahlqvist, J.R.; Oestergaard, S.T.; Poulsen, N.S.; Knak, K.L.; Thomsen, C.; Vissing, J. Muscle contractility in spinobulbar muscular atrophy. Sci. Rep. 2019, 9, 4680.
  27. Harding, A.E.; Thomas, P.K.; Baraitser, M.; Bradbury, P.G.; Morgan-Hughes, J.A.; Ponsford, J.R. X-linked recessive bulbospinal neuronopathy: A report of ten cases. J. Neurol. Neurosurg. Psychiatry 1982, 45, 1012–1019.
  28. Chahin, N.; Sorenson, E.J. Serum creatine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis. Muscle Nerve 2009, 40, 126–129.
  29. Sorenson, E.J.; Klein, C.J. Elevated creatine kinase and transaminases in asymptomatic SBMA. Amyotroph. Lateral Scler. 2007, 8, 62–64.
  30. Suzuki, K.; Katsuno, M.; Banno, H.; Takeuchi, Y.; Atsuta, N.; Ito, M.; Watanabe, H.; Yamashita, F.; Hori, N.; Nakamura, T.; et al. CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA. Brain 2008, 131, 229–239.
  31. Kim, H.; Lim, Y.M.; Lee, E.J.; Oh, Y.J.; Kim, K.K. Correlation between the CAG repeat size and electrophysiological findings in patients with spinal and bulbar muscular atrophy. Muscle Nerve 2018, 57, 683–686.
  32. Rhodes, L.E.; Freeman, B.K.; Auh, S.; Kokkinis, A.D.; La Pean, A.; Chen, C.; Lehky, T.J.; Shrader, J.A.; Levy, E.W.; Harris-Love, M.; et al. Clinical features of spinal and bulbar muscular atrophy. Brain 2009, 132, 3242–3251.
  33. Sathasivam, K.; Hobbs, C.; Turmaine, M.; Mangiarini, L.; Mahal, A.; Bertaux, F.; Wanker, E.E.; Doherty, P.; Davies, S.W.; Bates, G.P. Formation of polyglutamine inclusions in non-CNS tissue. Hum. Mol. Genet. 1999, 8, 813–822.
  34. Menalled, L.B.; Kudwa, A.E.; Miller, S.; Fitzpatrick, J.; Watson-Johnson, J.; Keating, N.; Ruiz, M.; Mushlin, R.; Alosio, W.; McConnell, K.; et al. Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington’s disease: zQ175. PLoS ONE 2012, 7, e49838.
  35. Huang, S.; Yang, S.; Guo, J.; Yan, S.; Gaertig, M.A.; Li, S.; Li, X.J. Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice. Cell Rep. 2015, 13, 196–208.
  36. Chivet, M.; Marchioretti, C.; Pirazzini, M.; Piol, D.; Scaramuzzino, C.; Polanco, M.J.; Romanello, V.; Zuccaro, E.; Parodi, S.; D’Antonio, M.; et al. Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism. Cells 2020, 9, 325.
  37. Yu, Z.; Dadgar, N.; Albertelli, M.; Gruis, K.; Jordan, C.; Robins, D.M.; Lieberman, A.P. Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model. J. Clin. Investig. 2006, 116, 2663–2672.
  38. Katsuno, M.; Adachi, H.; Kume, A.; Li, M.; Nakagomi, Y.; Niwa, H.; Sang, C.; Kobayashi, Y.; Doyu, M.; Sobue, G. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 2002, 35, 843–854.
  39. Ribchester, R.R.; Thomson, D.; Wood, N.I.; Hinks, T.; Gillingwater, T.H.; Wishart, T.M.; Court, F.A.; Morton, A.J. Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington’s disease mutation. Eur. J. Neurosci. 2004, 20, 3092–3114.
  40. Lodi, R.; Schapira, A.H.; Manners, D.; Styles, P.; Wood, N.W.; Taylor, D.J.; Warner, T.T. Abnormal in vivo skeletal muscle energy metabolism in Huntington’s disease and dentatorubropallidoluysian atrophy. Ann. Neurol. 2000, 48, 72–76.
  41. Strand, A.D.; Aragaki, A.K.; Shaw, D.; Bird, T.; Holton, J.; Turner, C.; Tapscott, S.J.; Tabrizi, S.J.; Schapira, A.H.; Kooperberg, C.; et al. Gene expression in Huntington’s disease skeletal muscle: A potential biomarker. Hum. Mol. Genet. 2005, 14, 1863–1876.
  42. Rocchi, A.; Milioto, C.; Parodi, S.; Armirotti, A.; Borgia, D.; Pellegrini, M.; Urciuolo, A.; Molon, S.; Morbidoni, V.; Marabita, M.; et al. Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet. Acta Neuropathol. 2016, 132, 127–144.
  43. Giorgetti, E.; Yu, Z.; Chua, J.P.; Shimamura, R.; Zhao, L.; Zhu, F.; Venneti, S.; Pennuto, M.; Guan, Y.; Hung, G.; et al. Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing. Cell Rep. 2016, 17, 125–136.
  44. Braubach, P.; Orynbayev, M.; Andronache, Z.; Hering, T.; Landwehrmeyer, G.B.; Lindenberg, K.S.; Melzer, W. Altered Ca(2+) signaling in skeletal muscle fibers of the R6/2 mouse, a model of Huntington’s disease. J. Gen. Physiol. 2014, 144, 393–413.
  45. Xu, Y.; Halievski, K.; Henley, C.; Atchison, W.D.; Katsuno, M.; Adachi, H.; Sobue, G.; Breedlove, S.M.; Jordan, C.L. Defects in Neuromuscular Transmission May Underlie Motor Dysfunction in Spinal and Bulbar Muscular Atrophy. J. Neurosci. 2016, 36, 5094–5106.
  46. Poort, J.E.; Rheuben, M.B.; Breedlove, S.M.; Jordan, C.L. Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy. Hum. Mol. Genet. 2016, 25, 3768–3783.
  47. Cortes, C.J.; Ling, S.C.; Guo, L.T.; Hung, G.; Tsunemi, T.; Ly, L.; Tokunaga, S.; Lopez, E.; Sopher, B.L.; Bennett, C.F.; et al. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron 2014, 82, 295–307.
  48. Monks, D.A.; Johansen, J.A.; Mo, K.; Rao, P.; Eagleson, B.; Yu, Z.; Lieberman, A.P.; Breedlove, S.M.; Jordan, C.L. Overexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease. Proc. Natl. Acad. Sci. USA 2007, 104, 18259–18264.
  49. Moffitt, H.; McPhail, G.D.; Woodman, B.; Hobbs, C.; Bates, G.P. Formation of polyglutamine inclusions in a wide range of non-CNS tissues in the HdhQ150 knock-in mouse model of Huntington’s disease. PLoS ONE 2009, 4, e8025.
  50. Kojer, K.; Hering, T.; Bazenet, C.; Weiss, A.; Herrmann, F.; Taanman, J.W.; Orth, M. Huntingtin Aggregates and Mitochondrial Pathology in Skeletal Muscle but not Heart of Late-Stage R6/2 Mice. J. Huntingtons Dis. 2019, 8, 145–159.
  51. Ciammola, A.; Sassone, J.; Alberti, L.; Meola, G.; Mancinelli, E.; Russo, M.A.; Squitieri, F.; Silani, V. Increased apoptosis, Huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington’s disease subjects. Cell Death Differ. 2006, 13, 2068–2078.
  52. Nath, S.R.; Lieberman, M.L.; Yu, Z.; Marchioretti, C.; Jones, S.T.; Danby, E.C.E.; Van Pelt, K.M.; Soraru, G.; Robins, D.M.; Bates, G.P.; et al. MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease. Acta Neuropathol. 2020, 140, 63–80.
  53. Badders, N.M.; Korff, A.; Miranda, H.C.; Vuppala, P.K.; Smith, R.B.; Winborn, B.J.; Quemin, E.R.; Sopher, B.L.; Dearman, J.; Messing, J.; et al. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. Nat. Med. 2018, 24, 427–437.
  54. Becanovic, K.; Asghar, M.; Gadawska, I.; Sachdeva, S.; Walker, D.; Lazarowski, E.R.; Franciosi, S.; Park, K.H.J.; Cote, H.C.F.; Leavitt, B.R. Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease. NPJ Aging Mech. Dis. 2021, 7, 26.
  55. Squitieri, F.; Cannella, M.; Sgarbi, G.; Maglione, V.; Falleni, A.; Lenzi, P.; Baracca, A.; Cislaghi, G.; Saft, C.; Ragona, G.; et al. Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation. Mech. Ageing Dev. 2006, 127, 217–220.
  56. Saft, C.; Zange, J.; Andrich, J.; Muller, K.; Lindenberg, K.; Landwehrmeyer, B.; Vorgerd, M.; Kraus, P.H.; Przuntek, H.; Schols, L. Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington’s disease. Mov. Disord. 2005, 20, 674–679.
  57. Borgia, D.; Malena, A.; Spinazzi, M.; Desbats, M.A.; Salviati, L.; Russell, A.P.; Miotto, G.; Tosatto, L.; Pegoraro, E.; Soraru, G.; et al. Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy patients. Hum. Mol. Genet. 2017, 26, 1087–1103.
  58. Ranganathan, S.; Harmison, G.G.; Meyertholen, K.; Pennuto, M.; Burnett, B.G.; Fischbeck, K.H. Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum. Mol. Genet. 2009, 18, 27–42.
  59. Pourshafie, N.; Masati, E.; Bunker, E.; Nickolls, A.R.; Thepmankorn, P.; Johnson, K.; Feng, X.; Ekins, T.; Grunseich, C.; Fischbeck, K.H. Linking epigenetic dysregulation, mitochondrial impairment, and metabolic dysfunction in SBMA motor neurons. JCI Insight 2020, 5, e136539.
  60. Beauchemin, A.M.; Gottlieb, B.; Beitel, L.K.; Elhaji, Y.A.; Pinsky, L.; Trifiro, M.A. Cytochrome c oxidase subunit Vb interacts with human androgen receptor: A potential mechanism for neurotoxicity in spinobulbar muscular atrophy. Brain Res. Bull. 2001, 56, 285–297.
  61. Orsucci, D.; Rocchi, A.; Caldarazzo Ienco, E.; Ali, G.; LoGerfo, A.; Petrozzi, L.; Scarpelli, M.; Filosto, M.; Carlesi, C.; Siciliano, G.; et al. Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases. Curr. Mol. Med. 2014, 14, 598–602.
  62. Luthi-Carter, R.; Hanson, S.A.; Strand, A.D.; Bergstrom, D.A.; Chun, W.; Peters, N.L.; Woods, A.M.; Chan, E.Y.; Kooperberg, C.; Krainc, D.; et al. Dysregulation of gene expression in the R6/2 model of polyglutamine disease: Parallel changes in muscle and brain. Hum. Mol. Genet. 2002, 11, 1911–1926.
  63. Hering, T.; Braubach, P.; Landwehrmeyer, G.B.; Lindenberg, K.S.; Melzer, W. Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease. PLoS ONE 2016, 11, e0166106.
  64. Cox, H.; Costin-Kelly, N.M.; Ramani, P.; Whitehouse, W.P. An established case of dentatorubral pallidoluysian atrophy (DRPLA) with unusual features on muscle biopsy. Eur. J. Paediatr. Neurol. 2000, 4, 119–123.
  65. She, P.; Zhang, Z.; Marchionini, D.; Diaz, W.C.; Jetton, T.J.; Kimball, S.R.; Vary, T.C.; Lang, C.H.; Lynch, C.J. Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington’s disease. Am. J. Physiol. Endocrinol. Metab. 2011, 301, E49–E61.
  66. Sartori, R.; Romanello, V.; Sandri, M. Mechanisms of muscle atrophy and hypertrophy: Implications in health and disease. Nat. Commun. 2021, 12, 330.
  67. Cortes, C.J.; Miranda, H.C.; Frankowski, H.; Batlevi, Y.; Young, J.E.; Le, A.; Ivanov, N.; Sopher, B.L.; Carromeu, C.; Muotri, A.R.; et al. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat. Neurosci. 2014, 17, 1180–1189.
  68. Magnusson-Lind, A.; Davidsson, M.; Silajdzic, E.; Hansen, C.; McCourt, A.C.; Tabrizi, S.J.; Bjorkqvist, M. Skeletal muscle atrophy in R6/2 mice—altered circulating skeletal muscle markers and gene expression profile changes. J. Huntingt. Dis. 2014, 3, 13–24.
  69. Mielcarek, M.; Toczek, M.; Smeets, C.J.; Franklin, S.A.; Bondulich, M.K.; Jolinon, N.; Muller, T.; Ahmed, M.; Dick, J.R.; Piotrowska, I.; et al. HDAC4-myogenin axis as an important marker of HD-related skeletal muscle atrophy. PLoS Genet. 2015, 11, e1005021.
  70. Miranda, D.R.; Wong, M.; Romer, S.H.; McKee, C.; Garza-Vasquez, G.; Medina, A.C.; Bahn, V.; Steele, A.D.; Talmadge, R.J.; Voss, A.A. Progressive Cl- channel defects reveal disrupted skeletal muscle maturation in R6/2 Huntington’s mice. J. Gen. Physiol. 2017, 149, 55–74.
  71. Miranda, D.R.; Reed, E.; Jama, A.; Bottomley, M.; Ren, H.; Rich, M.M.; Voss, A.A. Mechanisms of altered skeletal muscle action potentials in the R6/2 mouse model of Huntington’s disease. Am. J. Physiol. Cell Physiol. 2020, 319, C218–C232.
  72. Malena, A.; Pennuto, M.; Tezze, C.; Querin, G.; D’Ascenzo, C.; Silani, V.; Cenacchi, G.; Scaramozza, A.; Romito, S.; Morandi, L.; et al. Androgen-dependent impairment of myogenesis in spinal and bulbar muscular atrophy. Acta Neuropathol. 2013, 126, 109–121.
  73. Mueller, S.M.; Mihaylova, V.; Frese, S.; Petersen, J.A.; Ligon-Auer, M.; Aguayo, D.; Fluck, M.; Jung, H.H.; Toigo, M. Satellite cell content in Huntington’s disease patients in response to endurance training. Orphanet. J. Rare Dis. 2019, 14, 135.
  74. Al Tanoury, Z.; Rao, J.; Tassy, O.; Gobert, B.; Gapon, S.; Garnier, J.M.; Wagner, E.; Hick, A.; Hall, A.; Gussoni, E.; et al. Differentiation of the human PAX7-positive myogenic precursors/satellite cell lineage in vitro. Development 2020, 147, dev187344.
  75. Kwon, J.B.; Vankara, A.; Ettyreddy, A.R.; Bohning, J.D.; Gersbach, C.A. Myogenic Progenitor Cell Lineage Specification by CRISPR/Cas9-Based Transcriptional Activators. Stem Cell Rep. 2020, 14, 755–769.
  76. Yoshioka, K.; Ito, A.; Kawabe, Y.; Kamihira, M. Novel neuromuscular junction model in 2D and 3D myotubes co-cultured with induced pluripotent stem cell-derived motor neurons. J. Biosci. Bioeng. 2020, 129, 486–493.
  77. Rao, L.; Qian, Y.; Khodabukus, A.; Ribar, T.; Bursac, N. Engineering human pluripotent stem cells into a functional skeletal muscle tissue. Nat. Commun. 2018, 9, 126.
  78. Maffioletti, S.M.; Sarcar, S.; Henderson, A.B.H.; Mannhardt, I.; Pinton, L.; Moyle, L.A.; Steele-Stallard, H.; Cappellari, O.; Wells, K.E.; Ferrari, G.; et al. Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering. Cell Rep. 2018, 23, 899–908.
  79. Jiwlawat, S.; Lynch, E.; Glaser, J.; Smit-Oistad, I.; Jeffrey, J.; Van Dyke, J.M.; Suzuki, M. Differentiation and sarcomere formation in skeletal myocytes directly prepared from human induced pluripotent stem cells using a sphere-based culture. Differentiation 2017, 96, 70–81.
  80. O’Regan, G.C.; Farag, S.H.; Casey, C.S.; Wood-Kaczmar, A.; Pocock, J.M.; Tabrizi, S.J.; Andre, R. Human Huntington’s disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species. J. Neuroinflamm. 2021, 18, 94.
  81. Sheila, M.; Narayanan, G.; Ma, S.; Tam, W.L.; Chai, J.; Stanton, L.W. Phenotypic and molecular features underlying neurodegeneration of motor neurons derived from spinal and bulbar muscular atrophy patients. Neurobiol. Dis. 2019, 124, 1–13.
  82. Burman, R.J.; Watson, L.M.; Smith, D.C.; Raimondo, J.V.; Ballo, R.; Scholefield, J.; Cowley, S.A.; Wood, M.J.A.; Kidson, S.H.; Greenberg, L.J. Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells. PLoS ONE 2021, 16, e0247434.
  83. Lim, R.G.; Quan, C.; Reyes-Ortiz, A.M.; Lutz, S.E.; Kedaigle, A.J.; Gipson, T.A.; Wu, J.; Vatine, G.D.; Stocksdale, J.; Casale, M.S.; et al. Huntington’s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits. Cell Rep. 2017, 19, 1365–1377.
  84. Mattis, V.B.; Tom, C.; Akimov, S.; Saeedian, J.; Ostergaard, M.E.; Southwell, A.L.; Doty, C.N.; Ornelas, L.; Sahabian, A.; Lenaeus, L.; et al. HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity. Hum. Mol. Genet. 2015, 24, 3257–3271.
  85. Jian, Q.; Miao, Y.; Tang, L.; Huang, M.; Yang, Y.; Ba, W.; Liu, Y.; Chi, S.; Li, C. Rab23 promotes squamous cell carcinoma cell migration and invasion via integrin beta1/Rac1 pathway. Oncotarget 2016, 7, 5342–5352.
  86. Juopperi, T.A.; Kim, W.R.; Chiang, C.H.; Yu, H.; Margolis, R.L.; Ross, C.A.; Ming, G.L.; Song, H. Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington’s disease patient cells. Mol. Brain 2012, 5, 17.
  87. Bondulich, M.K.; Jolinon, N.; Osborne, G.F.; Smith, E.J.; Rattray, I.; Neueder, A.; Sathasivam, K.; Ahmed, M.; Ali, N.; Benjamin, A.C.; et al. Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington’s disease mice. Sci. Rep. 2017, 7, 14275.
  88. Sjogren, M.; Duarte, A.I.; McCourt, A.C.; Shcherbina, L.; Wierup, N.; Bjorkqvist, M. Ghrelin rescues skeletal muscle catabolic profile in the R6/2 mouse model of Huntington’s disease. Sci. Rep. 2017, 7, 13896.
  89. Lieberman, A.P.; Yu, Z.; Murray, S.; Peralta, R.; Low, A.; Guo, S.; Yu, X.X.; Cortes, C.J.; Bennett, C.F.; Monia, B.P.; et al. Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy. Cell Rep. 2014, 7, 774–784.
  90. Palazzolo, I.; Stack, C.; Kong, L.; Musaro, A.; Adachi, H.; Katsuno, M.; Sobue, G.; Taylor, J.P.; Sumner, C.J.; Fischbeck, K.H.; et al. Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Neuron 2009, 63, 316–328.
  91. Rinaldi, C.; Bott, L.C.; Chen, K.L.; Harmison, G.G.; Katsuno, M.; Sobue, G.; Pennuto, M.; Fischbeck, K.H. Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy. Mol. Med. 2012, 18, 1261–1268.
  92. Milioto, C.; Malena, A.; Maino, E.; Polanco, M.J.; Marchioretti, C.; Borgia, D.; Pereira, M.G.; Blaauw, B.; Lieberman, A.P.; Venturini, R.; et al. Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes. Sci. Rep. 2017, 7, 41046.
  93. Querin, G.; D’Ascenzo, C.; Peterle, E.; Ermani, M.; Bello, L.; Melacini, P.; Morandi, L.; Mazzini, L.; Silani, V.; Raimondi, M.; et al. Pilot trial of clenbuterol in spinal and bulbar muscular atrophy. Neurology 2013, 80, 2095–2098.
  94. Soraru, G.; Pegoraro, E.; Spinella, P.; Turra, S.; D’Ascenzo, C.; Baggio, L.; Mantovan, M.C.; Vergani, L.; Angelini, C. A pilot trial with clenbuterol in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 2006, 7, 246–248.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Neurosciences; 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 :
Caterina Marchioretti
,
Emanuela Zuccaro
,
Udai Bhan Pandey
,
Jessica Rosati
,
Manuela Basso
,
Maria Pennuto
View Times: 481
Entry Collection: Neurodegeneration
Revisions: 3 times (View History)
Update Date: 28 Jul 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback