When lamins go bad: nuclear structure and disease.

Mutations in nuclear lamins or other proteins of the nuclear envelope are the root cause of a group of phenotypically diverse genetic disorders known as laminopathies, which have symptoms that range from muscular dystrophy to neuropathy to premature aging syndromes. Although precise disease mechanisms remain unclear, there has been substantial progress in our understanding of not only laminopathies, but also the biological roles of nuclear structure. Nuclear envelope dysfunction is associated with altered nuclear activity, impaired structural dynamics, and aberrant cell signaling. Building on these findings, small molecules are being discovered that may become effective therapeutic agents.

Structure of the rigor actin-tropomyosin-myosin complex.

Regulation of myosin and filamentous actin interaction by tropomyosin is a central feature of contractile events in muscle and nonmuscle cells. However, little is known about molecular interactions within the complex and the trajectory of tropomyosin movement between its "open" and "closed" positions on the actin filament. Here, we report the 8 Å resolution structure of the rigor (nucleotide-free) actin-tropomyosin-myosin complex determined by cryo-electron microscopy. The pseudoatomic model of the complex, obtained from fitting crystal structures into the map, defines the large interface involving two adjacent actin monomers and one tropomyosin pseudorepeat per myosin contact. Severe forms of hereditary myopathies are linked to mutations that critically perturb this interface. Myosin binding results in a 23 Å shift of tropomyosin along actin. Complex domain motions occur in myosin, but not in actin. Based on our results, we propose a structural model for the tropomyosin-dependent modulation of myosin binding to actin.

ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97.

Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43-positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP's activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in Ulk1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.

Sarcopenia: Aging-Related Loss of Muscle Mass and Function.

Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and extended rehabilitation. This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of the α-motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates. Loss of muscle mass with aging, which is largely due to the progressive loss of motoneurons, is associated with reduced muscle fiber number and size. Muscle function progressively declines because motoneuron loss is not adequately compensated by reinnervation of muscle fibers by the remaining motoneurons. At the intracellular level, key factors are qualitative changes in posttranslational modifications of muscle proteins and the loss of coordinated control between contractile, mitochondrial, and sarcoplasmic reticulum protein expression. Quantitative and qualitative changes in skeletal muscle during the process of aging also have been implicated in the pathogenesis of acquired and hereditary neuromuscular disorders. In experimental models, specific intervention strategies have shown encouraging results on limiting deterioration of motor unit structure and function under conditions of impaired innervation. Translated to the clinic, if these or similar interventions, by saving muscle and improving mobility, could help alleviate sarcopenia in the elderly, there would be both great humanitarian benefits and large cost savings for health care systems.

RIG-I Uses an ATPase-Powered Translocation-Throttling Mechanism for Kinetic Proofreading of RNAs and Oligomerization.

RIG-I has a remarkable ability to specifically select viral 5'ppp dsRNAs for activation from a pool of cytosolic self-RNAs. The ATPase activity of RIG-I plays a role in RNA discrimination and activation, but the underlying mechanism was unclear. Using transient-state kinetics, we elucidated the ATPase-driven "kinetic proofreading" mechanism of RIG-I activation and RNA discrimination, akin to DNA polymerases, ribosomes, and T cell receptors. Even in the autoinhibited state of RIG-I, the C-terminal domain kinetically discriminates against self-RNAs by fast off rates. ATP binding facilitates dsRNA engagement but, interestingly, makes RIG-I promiscuous, explaining the constitutive signaling by Singleton-Merten syndrome-linked mutants that bind ATP without hydrolysis. ATP hydrolysis dissociates self-RNAs faster than 5'ppp dsRNA but, more importantly, drives RIG-I oligomerization through translocation, which we show to be regulated by helicase motif IVa. RIG-I translocates directionally from the dsRNA end into the stem region, and the 5'ppp end "throttles" translocation to provide a mechanism for threading and building a signaling-active oligomeric complex.

Sarcopenia phenotype and impaired muscle function in male mice with fast-twitch muscle-specific knockout of the androgen receptor.

Sarcopenia is distinct from normal muscle atrophy in that it is closely related to a shift in the muscle fiber type. Deficiency of the anabolic action of androgen on skeletal muscles is associated with sarcopenia; however, the function of the androgen receptor (AR) pathway in sarcopenia remains poorly understood. We generated a mouse model (fast-twitch muscle-specific AR knockout [fmARKO] mice) in which the AR was selectively deleted in the fast-twitch muscle fibers. In young male mice, the deletion caused no change in muscle mass, but it reduced muscle strength and fatigue resistance and induced a shift in the soleus muscles from fast-twitch fibers to slow-twitch fibers (14% increase, P = 0.02). After middle age, with the control mice, the male fmARKO mice showed much less muscle function, accompanied by lower hindlimb muscle mass; this phenotype was similar to the progression of sarcopenia. The bone mineral density of the femur was significantly reduced in the fmARKO mice, indicating possible osteosarcopenia. Microarray and gene ontology analyses revealed that in male fmARKO mice, there was downregulation of polyamine biosynthesis-related geneswhich was confirmed by liquid chromatography-tandem mass spectrometry assay and the primary cultured myofibers. None of the AR deletion-related phenotypes were observed in female fmARKO mice. Our findings showed that the AR pathway had essential muscle type- and sex-specific roles in the differentiation toward fast-twitch fibers and in the maintenance of muscle composition and function. The AR in fast-twitch muscles was the dominant regulator of muscle fiber-type composition and muscle function, including the muscle-bone relationship.

Mechanochemical consequences of myopathy-linked mutations in Tpm2.2 on striated muscle contractility.

Tropomyosin (Tpm) is an actin-binding protein central to muscle contraction regulation. The Tpm sequence consists of periodic repeats corresponding to seven actin-binding sites, further divided in two functionally distinct halves. To clarify the importance of the first and second halves of the actin-binding periods in regulating the interaction of myosin with actin, we introduced hypercontractile mutations D20H, E181K located in the N-terminal halves of periods 1 and 5 and hypocontractile mutations E41K, N202K located in the C-terminal halves of periods 1 and 5 of the skeletal muscle Tpm isoform Tpm2.2. Wild-type and mutant Tpms displayed similar actin-binding properties, however, as revealed by FRET experiments, the hypercontractile mutations affected the binding geometry and orientation of Tpm2.2 on actin, causing a stimulation of myosin motor performance. Contrary, the hypocontractile mutations led to an inhibition of both, actin activation of the myosin ATPase and motor activity, that was more pronounced than with wild-type Tpm2.2. Single ATP turnover kinetic experiments indicate that the introduced mutations have opposite effects on product release kinetics. While the hypercontractile Tpm2.2 mutants accelerated product release, the hypocontractile mutants decelerated product release from myosin, thus having either an activating or inhibitory influence on myosin motor performance, which agrees with the muscle disease phenotypes caused by these mutations.

Activation of the Aryl Hydrocarbon Receptor in Muscle Exacerbates Ischemic Pathology in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD. Herein, we examined the role of AHR activation in the myopathy of PAD and CKD. METHODS: AHR-related gene expression was evaluated in skeletal muscle obtained from mice and human PAD patients with and without CKD. AHRmKO (skeletal muscle-specific AHR knockout) mice with and without CKD were subjected to femoral artery ligation, and a battery of assessments were performed to evaluate vascular, muscle, and mitochondrial health. Single-nuclei RNA sequencing was performed to explore intercellular communication. Expression of the constitutively active AHR was used to isolate the role of AHR in mice without CKD. RESULTS: PAD patients and mice with CKD displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1, Cyp1b1, and Aldh3a1) when compared with either muscle from the PAD condition with normal renal function (P<0.05 for all 3 genes) or nonischemic controls. AHRmKO significantly improved limb perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and strength, as well as enhanced mitochondrial function in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. CONCLUSIONS: These findings establish AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in CKD. Further, the totality of the results provides support for testing of clinical interventions that diminish AHR signaling in these conditions.

Muscle stem cells get a new look: Dynamic cellular projections as sensors of the stem cell niche.

Cellular mechanisms whereby quiescent stem cells sense tissue injury and transition to an activated state are largely unknown. Quiescent skeletal muscle stem cells (MuSCs, also called satellite cells) have elaborate, heterogeneous projections that rapidly retract in response to muscle injury. They may therefore act as direct sensors of their niche environment. Retraction is driven by a Rac-to-Rho GTPase activity switch that promotes downstream MuSC activation events. These and other observations lead to several hypotheses: (1) projections are morphologically dynamic at quiescence, providing a surveillance function for muscle damage; (2) quiescent projection dynamics are regulated by the relative balance of Rac and Rho activities promoted by niche-derived cues; (3) projections, particularly their associated filopodia, sense tissue damage via changes to the biomechanical properties of the niche and/or detection of signaling cues released by damaged myofibers; and (4) the dynamic nature of projections results in a population of MuSCs with heterogeneous functional properties. These concepts may extend to other types of quiescent stem cells, as well as prove useful in translational research settings.

Genetic dissection of novel myopathy models reveals a role of CapZα and Leiomodin 3 during myofibril elongation.

Myofibrils within skeletal muscle are composed of sarcomeres that generate force by contraction when their myosin-rich thick filaments slide past actin-based thin filaments. Although mutations in components of the sarcomere are a major cause of human disease, the highly complex process of sarcomere assembly is not fully understood. Current models of thin filament assembly highlight a central role for filament capping proteins, which can be divided into three protein families, each ascribed with separate roles in thin filament assembly. CapZ proteins have been shown to bind the Z-disc protein α-actinin to form an anchoring complex for thin filaments and actin polymerisation. Subsequent thin filaments extension dynamics are thought to be facilitated by Leiomodins (Lmods) and thin filament assembly is concluded by Tropomodulins (Tmods) that specifically cap the pointed end of thin filaments. To study thin filament assembly in vivo, single and compound loss-of-function zebrafish mutants within distinct classes of capping proteins were analysed. The generated lmod3- and capza1b-deficient zebrafish exhibited aspects of the pathology caused by variations in their human orthologs. Although loss of the analysed main capping proteins of the skeletal muscle, capza1b, capza1a, lmod3 and tmod4, resulted in sarcomere defects, residual organised sarcomeres were formed within the assessed mutants, indicating that these proteins are not essential for the initial myofibril assembly. Furthermore, detected similarity and location of myofibril defects, apparent at the peripheral ends of myofibres of both Lmod3- and CapZα-deficient mutants, suggest a function in longitudinal myofibril growth for both proteins, which is molecularly distinct to the function of Tmod4.

Evaluation of skeletal muscle function in male rats with doxorubicin-induced myopathy following various exercise techniques: the significant role of glucose transporter 4.

A common anthracycline antibiotic used to treat cancer patients is doxorubicin (DOX). One of the effects of DOX therapy is skeletal muscle fatigue. Our goal in this research was to study the beneficial effect of exercise on DOX-induced damaged muscle fibers and compare the effect of different exercise strategies (prophylactic, post- toxicity and combined) on DOX toxicity. Five groups were created from 40 male rats: group I, control group; group II, DOX was administered intraperitoneally for 2 weeks over 6 equal injections (each 2.5 mg/kg); group III, rats trained for 3 weeks before DOX; group IV, rats trained for 8 weeks after DOX; and group V, rats were trained for 3 weeks before DOX followed by 8 weeks after. Measures of oxidative damage (H2O2, catalase), inflammation (TNF-α), and glucose transporter 4 (GLUT4) expression on skeletal muscle were assessed. Also, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was estimated. Skeletal performance was evaluated by contraction time (CT), half relaxation time (1/2 RT), and force-frequency relationship by the end of this research. The current study demonstrated a detrimental effect of DOX on skeletal performance as evidenced by a significant increase in CT and 1/2 RT compared to control; in addition, H2O2, TNF-α, and HOMA-IR were significantly increased with a significant decrease in GLUT4 expression and catalase activity. Combined exercise therapy showed a remarkable improvement in skeletal muscle performance, compared to DOX, CT, and 1/2 RT which were significantly decreased; H2O2 and TNF-α were significantly decreased unlike catalase antioxidant activity that significantly increased; in addition, skeletal muscle glucose metabolism was significantly improved as GLUT4 expression significantly increased and HOMA-IR was significantly decreased. Exercise therapy showed significant improvement in all measured parameters relative to DOX. However, combined exercise therapy showed the best improvement relative to both pre-exercise and post-exercise groups.

Photobiomodulation therapy moderates cancer cachexia-associated muscle wasting through activating PI3K/AKT/FoxO3a pathway.

Cancer cachexia-associated muscle wasting as a multifactorial wasting syndrome, is an important factor affecting the long-term survival rate of tumor patients. Photobiomodulation therapy (PBMT) has emerged as a promising tool to cure and prevent many diseases. However, the effect of PBMT on skeletal muscle atrophy during cancer progression has not been fully demonstrated yet. Here, we found PBMT alleviated the atrophy of myotube diameter induced by cancer cells in vitro, and prevented cancer-associated muscle atrophy in mice bearing tumor. Mechanistically, the alleviation of muscle wasting by PBMT was found to be involved in inhibiting E3 ubiquitin ligases MAFbx and MuRF-1. In addition, transcriptomic analysis using RNA-seq and GSEA revealed that PI3K/AKT pathway might be involved in PBMT-prevented muscle cachexia. Next, we showed the protective effect of PBMT against muscle cachexia was totally blocked by AKT inhibitor in vitro and in vivo. Moreover, PBMT-activated AKT promoted FoxO3a phosphorylation and thus inhibiting the nucleus entry of FoxO3a. Lastly, in cisplatin-treated muscle cachexia model, PBMT had also been shown to ameliorate muscle atrophy through enhancing PI3K/AKT pathway to suppress MAFbx and MuRF-1 expression. These novel findings revealed that PBMT could be a promising therapeutic approach in treating muscle cachexia induced by cancer.

Deubiquitinases in muscle physiology and disorders.

In vivo, muscle and neuronal cells are post-mitotic, and their function is predominantly regulated by proteostasis, a multilayer molecular process that maintains a delicate balance of protein homeostasis. The ubiquitin-proteasome system (UPS) is a key regulator of proteostasis. A dysfunctional UPS is a hallmark of muscle ageing and is often impacted in neuromuscular disorders (NMDs). Malfunction of the UPS often results in aberrant protein accumulation which can lead to protein aggregation and/or mis-localization affecting its function. Deubiquitinating enzymes (DUBs) are key players in the UPS, controlling protein turnover and maintaining the free ubiquitin pool. Several mutations in DUB encoding genes are linked to human NMDs, such as ATXN3, OTUD7A, UCHL1 and USP14, whilst other NMDs are associated with dysregulation of DUB expression. USP5, USP9X and USP14 are implicated in synaptic transmission and remodeling at the neuromuscular junction. Mice lacking USP19 show increased maintenance of lean muscle mass. In this review, we highlight the involvement of DUBs in muscle physiology and NMDs, particularly in processes affecting muscle regeneration, degeneration and inflammation following muscle injury. DUBs have recently garnered much respect as promising drug targets, and their roles in muscle maturation, regeneration and degeneration may provide the framework for novel therapeutics to treat muscular disorders including NMDs, sarcopenia and cachexia.

Skeletal muscle involvement in systemic amyloidosis is often overlooked.

AIM: Systemic amyloidosis is a condition in which misfolded amyloid fibrils are deposited within tissues. Amyloid myopathy is a rare manifestation of systemic amyloidosis. However, whether skeletal muscle involvement is underestimated and whether such deposition guarantees clinical and pathological myopathic features remain to be investigated. METHODS: We retrospectively reviewed patients with systemic amyloidosis, in whom skeletal muscle biopsies were performed at our centre between January 2018 and June 2023. In total, 28 patients with suspected systemic amyloidosis were included. Among these, 21 presented with cardiomyopathy but lacked myopathic symptoms. The clinical and pathological data of these patients were further analysed. The amyloid type was confirmed by immunohistochemistry. RESULTS: Twenty-eight patients with suspected systemic amyloidosis underwent muscle biopsy. Amyloid deposition in the skeletal muscle was confirmed in 24 patients, including 22 with light-chain amyloidosis (AL) and two with transthyretin amyloidosis (ATTR). Among the 24 patients, seven presented with muscle weakness and decreased muscle strength (Group 1, symptomatic myopathy), whereas the remaining 17 exhibited normal muscle strength (Group 2, asymptomatic myopathy). Group 1 included four patients with AL-λ, one with AL-κ and two with ATTR. Group 2 included 15 patients with AL-λ and two patients with AL-κ. In Group 1, six patients exhibited neuropathy, whereas only one patient in Group 2 presented with subclinical neuropathy on nerve conduction studies. Amyloid deposition in the interstitium was the most obvious change, observed in all 24 patients. Neuropathic changes, including denervation atrophy and muscle fibre grouping, were also common. Except for type 2 fibre atrophy, the other myopathic changes were mild and nonspecific. No sarcolemmal disruption was observed. Immunohistochemical analysis revealed marked positivity for MAC and MHC1 expression in the regions with amyloid deposits. Clinicopathological analysis revealed no significant differences in the extent of muscular amyloid deposition between the two groups. Nevertheless, patients in Group 1 displayed more pronounced neurogenic atrophy on skeletal muscle biopsies. CONCLUSIONS: Our study indicates that amyloid deposition in skeletal muscle is commonly observed but rarely causes symptomatic myopathy in systemic amyloidosis.

Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle.

AIMS: Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin-1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin-1 deficiency. METHODS: We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy. RESULTS: The muscle tissue exhibited a complete absence of glycogenin-1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo-exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen. CONCLUSIONS: The absence of glycogenin-1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders.

Dantrolene and coenzyme Q10 as a suggested combination therapy to statin-induced myopathy in high fat diet rats: A possible interference with ROS/ TGF-ß / Smad4 signaling pathway.

One of the major hitches for statins' utilization is the development of myotoxicity. Versatile studies reported that the underlining molecular mechanisms including coenzyme Q10 (CoQ10)/ubiquinone depletion, as well as the disturbance in the cytoplasmic Ca2+ homeostasis. Therefore, we investigated the consequences of supplementing CoQ10 and dantrolene, a cytoplasmic Ca2+ reducing agent, in combination with simvastatin. This adjuvant therapy normalized the simvastatin-mediated elevation in serum ALT, AST, CK-MM, as well as tissue Ca2+ content, in addition to suppressing the simvastatin-mediated oxidative stress in simvastatin-treated rats, while having no effect upon statin-induced antihyperlipidemic effect. Additionally, the combination inhibited the simvastatin-induced TGF-ß/ Smad4 pathway activation. Collectively, the current study emphasizes on the potential utilization of dantrolene and CoQ10 as an adjuvant therapy to statins treatment for improving their side effect profile.

Cathepsin S deficiency improves muscle mass loss and dysfunction via the modulation of protein metabolism in mice under pathological stress conditions.

Cathepsin S (CTSS) is a widely expressed cysteinyl protease that has garnered attention because of its enzymatic and non-enzymatic functions under inflammatory and metabolic pathological conditions. Here, we examined whether CTSS participates in stress-related skeletal muscle mass loss and dysfunction, focusing on protein metabolic imbalance. Eight-week-old male wildtype (CTSS+/+ ) and CTSS-knockout (CTSS-/- ) mice were randomly assigned to non-stress and variable-stress groups for 2 weeks, and then processed for morphological and biochemical studies. Compared with non-stressed mice, stressed CTSS+/+ mice showed significant losses of muscle mass, muscle function, and muscle fiber area. In this setting, the stress-induced harmful changes in the levels of oxidative stress-related (gp91phox and p22phox ,), inflammation-related (SDF-1, CXCR4, IL-1ß, TNF-α, MCP-1, ICAM-1, and VCAM-1), mitochondrial biogenesis-related (PPAR-γ and PGC-1α) genes and/or proteins and protein metabolism-related (p-PI3K, p-Akt, p-FoxO3α, MuRF-1, and MAFbx1) proteins; and these alterations were rectified by CTSS deletion. Metabolomic analysis revealed that stressed CTSS-/- mice exhibited a significant improvement in the levels of glutamine metabolism pathway products. Thus, these findings indicated that CTSS can control chronic stress-related skeletal muscle atrophy and dysfunction by modulating protein metabolic imbalance, and thus CTSS was suggested to be a promising new therapeutic target for chronic stress-related muscular diseases.

Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction.

This review presents a comprehensive exploration of the pivotal role played by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, with a particular focus on Nesprin proteins, in cellular mechanics and the pathogenesis of muscular diseases. Distinguishing itself from prior works, the analysis delves deeply into the intricate interplay of the LINC complex, emphasizing its indispensable contribution to maintaining cellular structural integrity, especially in mechanically sensitive tissues such as cardiac and striated muscles. Additionally, the significant association between mutations in Nesprin proteins and the onset of Dilated Cardiomyopathy (DCM) and Emery-Dreifuss Muscular Dystrophy (EDMD) is highlighted, underscoring their pivotal role in disease pathogenesis. Through a comprehensive examination of DCM and EDMD cases, the review elucidates the disruptions in the LINC complex, nuclear morphology alterations, and muscular developmental disorders, thus emphasizing the essential function of an intact LINC complex in preserving muscle physiological functions. Moreover, the review provides novel insights into the implications of Nesprin mutations for cellular dynamics in the pathogenesis of muscular diseases, particularly in maintaining cardiac structural and functional integrity. Furthermore, advanced therapeutic strategies, including rectifying Nesprin gene mutations, controlling Nesprin protein expression, enhancing LINC complex functionality, and augmenting cardiac muscle cell function are proposed. By shedding light on the intricate molecular mechanisms underlying nuclear-cytoskeletal interactions, the review lays the groundwork for future research and therapeutic interventions aimed at addressing genetic muscle disorders.

Myostatin's marvels: From muscle regulator to diverse implications in health and disease.

Myostatin, a member of the transforming growth factor-ß superfamily, is a pivotal regulator of skeletal muscle growth in mammals. Its discovery has sparked significant interest due to its multifaceted roles in various physiological processes and its potential therapeutic implications. This review explores the diverse functions of myostatin in skeletal muscle development, maintenance and pathology. We delve into its regulatory mechanisms, including its interaction with other signalling pathways and its modulation by various factors such as microRNAs and mechanical loading. Furthermore, we discuss the therapeutic strategies aimed at targeting myostatin for the treatment of muscle-related disorders, including cachexia, muscular dystrophy and heart failure. Additionally, we examine the impact of myostatin deficiency on craniofacial morphology and bone development, shedding light on its broader implications beyond muscle biology. Through a comprehensive analysis of the literature, this review underscores the importance of further research into myostatin's intricate roles and therapeutic potential in human health and disease.

Adipocyte Rnf20 ablation increases the fast-twitch fibers of skeletal muscle via lysophosphatidylcholine 16:0.

Both adipose tissue and skeletal muscle are highly dynamic tissues and interact at the metabolic and hormonal levels in response to internal and external stress, and they coordinate in maintaining whole-body metabolic homeostasis. In our previous study, we revealed that adipocyte-specific Rnf20 knockout mice (ASKO mice) exhibited lower fat mass but higher lean mass, providing a good model for investigating the adipose-muscle crosstalk and exploring the effect of the adipocyte Rnf20 gene on the physiology and metabolism of skeletal muscle. Here, we confirmed that ASKO mice exhibited the significantly increased body weight and gastrocnemius muscle weight. Fiber-type switching in the soleus muscle of ASKO mice was observed, as evidenced by the increased number of fast-twitch fibers and decreased number of slow-twitch fibers. Serum metabolites with significant alteration in abundance were identified by metabolomic analysis and the elevated lysophosphatidylcholine 16:0 [LysoPC (16:0)] was observed in ASKO mice. In addition, lipidome analysis of gonadal white adipose tissue revealed a significant increase in LysoPCs and LysoPC (16:0) in ASKO mice. Furthermore, knockdown of Rnf20 gene in 3T3-L1 cells significantly increased the secretion of LysoPC, suggesting that LysoPC might be a critical metabolite in the adipose-muscle crosstalk of ASKO mice. Furthermore, in vitro study demonstrated that LysoPC (16:0) could induce the expression of fast-twitch muscle fibers related genes in differentiated C2C12 cells, indicating its potential role in adipose-muscle crosstalk. Taken together, these findings not only expand our understanding of the biological functions of Rnf20 gene in systemic lipid metabolism, but also provide insight into adipose tissue dysfunction-induced physiological alterations in skeletal muscle.