Skeletal Muscle Disease Research Articles

Sarcopenia in geriatric psychiatry: feasibility of the diagnostic process and estimation of prevalence within a hospital context.

BackgroundSarcopenia is an age‐related progressive and general skeletal muscle disease associated with negative consequences such as falls, disability, and mortality. An early‐stage diagnosis is important to enable adequate treatment, especially in geriatric psychiatry. However, there presently is little information about the feasibility of diagnostic procedures and the prevalence of sarcopenia in clinical geriatric psychiatry settings. The aim of this study is to implement a diagnostic process for sarcopenia in a geriatric psychiatry hospital, to investigate its feasibility and to analyse the prevalence rates.MethodsA single‐centre cross‐sectional study over 3 months was conducted in a geriatric psychiatry hospital. All admitted patients with a diagnosis of dementia, depression, or delirium were screened regarding the clinical impression of frailty and sarcopenia according to the current diagnostic algorithm of the European Working Group on Sarcopenia in Older People 2 (EWGSOP2).ResultsWe found that short physical performance tests, such as the handgrip strength testing (91%) or 4 m walking test (91%), were applicable in our sample. The original standardized instructions of longer tests could not be performed appropriately, for example, in the five‐times‐sit‐to‐stand‐test (32%), the timed‐up‐and‐go‐test (68%), and the 400 m walking test (38%). Muscle mass measurements using bioelectric impedance analysis were feasible in all patients (100%). The analysis revealed an estimated prevalence rate for sarcopenia of 65% for patients suffering from dementia and 36% for patients suffering from depression. In our final analysis, 15 patients suffering from dementia, 19 suffering from depression, and no patient suffering from delirium were included [22 female (64.7%) and twelve male (35.3%) patients]. The patients were on average 78.9 ± 7.7 years old, with the youngest patient being 61 years old and the oldest patient 93 years old. Out of the total sample, 14 patients suffering from dementia and eight patients suffering from depression were diagnosed with a severe stage of sarcopenia.ConclusionsThe EWGSOP2 algorithm seems to be applicable in the clinical routine of a geriatric psychiatry hospital. The high estimated prevalence rates of sarcopenia highlight the need for an early and comprehensive screening for sarcopenia in geriatric psychiatry.

Nigella Sativa-Coated Hydroxyapatite Scaffolds: Synergetic Cues to Stimulate Myoblasts Differentiation and Offset Infections.

At present osteoporosis has come into view as a major health concern. Skeletal diseases typified by weak and fragile bones have imposed threats of fissure. Hydroxyapatite (HAP) is known to induce osteoblast like differentiation and provide mechanical strength, hence, used in bone tissue engineering; whereas, Nigella sativa has also demonstrated potential to treat bone and muscle diseases. This study was aimed to develop potential orthopedic scaffold exploiting natural resources of Saudi Arabia which can be used as prospective tissue engineering implant. The bone scaffold was developed by grafting biogenic HAP with N. sativa essential oil. N. sativa was applied for boosting osteogenesis and to stimulate antimicrobial potential. Antimicrobial potential was investigated utilizing S. aureus bacteria. Spectroscopic and surface characters of N. sativa grafted HAP scaffolds were analyzed using Fourier-transform infrared spectroscopy, X-ray crystallography and Scanning electron microscopy. To ensure biocompatibility of scaffolds; we selected C2C12 cell-lines; best model to study mechanistic pathways related to osteoblasts and myoblasts differentiation. Grafting of HAP with N. sativa did not affect typical spherical silhouette of nanoparticles. Characteristically; protein loaded polynucleated myotubes are result of in vitro myogenesis of C2C12 myoblasts in squat serum environment. It is first study of unique combination of N. sativa and HAP scaffold as a possible candidate of implantation for skeletal muscles regeneration. Outcome of this finding revealed N. sativa grafted HAP enhance differentiation significantly over that of HAP. The proposed scaffold will be an economical natural material for hard and soft tissue engineering and will aid in curing skeletal muscle diseases. Our findings have implications for treatment of muscular/bone diseases.

A portable sitting posture monitoring system based on a pressure sensor array and machine learning

Poor sitting posture is one of the main inducements that lead to a series of skeletal muscle diseases. Sitting posture monitoring system can remind the user to maintain the correct sitting posture to prevent the harm of poor sitting posture to the body. In this paper, we proposed a portable sitting posture monitoring system to recognize the user's sitting posture and feedback the results in real time. A pressure sensor array is used to collect sitting postures related information, while the collected data can be displayed on a computer. The proposed system was designed to recognize seven types of sitting postures, including sitting upright, leaning forward, leaning backward, leaning left, leaning right, cross left leg, and cross right leg. Seven machine learning algorithms were implemented for comparation. The results showed that a five-layer Artificial Neural Network could achieve the highest accuracy of 97.07 %. To enhance system performance and reduce hardware cost, we further optimized the size of the sensor array. An 11 × 13 sensor array combined with Random Forest algorithm realized the optimal balance between classification accuracy (96.26 %) and hardware resource consumption. The final system prediction time is 19 us on the Raspberry Pi, which could satisfy the practical application requirement on the embedded platform.

Inherited Defects of the ASC-1 Complex in Congenital Neuromuscular Diseases.

Defects in transcriptional and cell cycle regulation have emerged as novel pathophysiological mechanisms in congenital neuromuscular disease with the recent identification of mutations in the TRIP4 and ASCC1 genes, encoding, respectively, ASC-1 and ASCC1, two subunits of the ASC-1 (Activating Signal Cointegrator-1) complex. This complex is a poorly known transcriptional coregulator involved in transcriptional, post-transcriptional or translational activities. Inherited defects in components of the ASC-1 complex have been associated with several autosomal recessive phenotypes, including severe and mild forms of striated muscle disease (congenital myopathy with or without myocardial involvement), but also cases diagnosed of motor neuron disease (spinal muscular atrophy). Additionally, antenatal bone fractures were present in the reported patients with ASCC1 mutations. Functional studies revealed that the ASC-1 subunit is a novel regulator of cell cycle, proliferation and growth in muscle and non-muscular cells. In this review, we summarize and discuss the available data on the clinical and histopathological phenotypes associated with inherited defects of the ASC-1 complex proteins, the known genotype–phenotype correlations, the ASC-1 pathophysiological role, the puzzling question of motoneuron versus primary muscle involvement and potential future research avenues, illustrating the study of rare monogenic disorders as an interesting model paradigm to understand major physiological processes.

High-intensity strength training in patients with idiopathic inflammatory myopathies: a randomised controlled trial protocol

IntroductionIdiopathic inflammatory myopathies (IIMs) are rare diseases characterised by non-suppurative inflammation of skeletal muscles and muscle weakness. Additionally, IIM is associated with a reduced quality of life. Strength training is...

New insights into molecular changes in skeletal muscle aging and disease: Differential alternative splicing and senescence

Progressive loss of muscle mass and function due to muscle fiber atrophy and loss in the elderly and chronically ill is now defined as sarcopenia. It is a major contributor to loss of independence, disability, need of long-term care as well as overall mortality. Sarcopenia is a heterogenous disease and underlying mechanisms are not completely understood. Here, we newly identified and used Tmem158, alongside Cdkn1a, as relevant senescence and denervation markers (SDMs), associated with muscle fiber atrophy. Subsequent application of laser capture microdissection (LCM) and RNA analyses revealed age- and disease-associated differences in gene expression and alternative splicing patterns in a rodent sarcopenia model. Of note, genes exhibiting such differential alternative splicing (DAS) are mainly involved in the contractile function of the muscle. Many of these splicing events are also found in a mouse model for myotonic dystrophy type 1 (DM1), underscoring the premature aging phenotype of this disease. We propose to add differential alternative splicing to the hallmarks of aging.

Role of Matricellular CCN Proteins in Skeletal Muscle: Focus on CCN2/CTGF and Its Regulation by Vasoactive Peptides.

The Cellular Communication Network (CCN) family of matricellular proteins comprises six proteins that share conserved structural features and play numerous biological roles. These proteins can interact with several receptors or soluble proteins, regulating cell signaling pathways in various tissues under physiological and pathological conditions. In the skeletal muscle of mammals, most of the six CCN family members are expressed during embryonic development or in adulthood. Their roles during the adult stage are related to the regulation of muscle mass and regeneration, maintaining vascularization, and the modulation of skeletal muscle fibrosis. This work reviews the CCNs proteins’ role in skeletal muscle physiology and disease, focusing on skeletal muscle fibrosis and its regulation by Connective Tissue Growth factor (CCN2/CTGF). Furthermore, we review evidence on the modulation of fibrosis and CCN2/CTGF by the renin-angiotensin system and the kallikrein-kinin system of vasoactive peptides.

Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin.

ΔR4-R23/ΔCT micro-dystrophin (μDys) is a miniaturized version of dystrophin currently evaluated in a Duchenne muscular dystrophy (DMD) gene therapy trial to treat skeletal and cardiac muscle disease. In pre-clinical studies, μDys efficiently rescues cardiac histopathology, but only partially normalizes cardiac function. To gain insights into factors that may impact the cardiac therapeutic efficacy of μDys, we compared by mass spectrometry the composition of purified dystrophin and μDys protein complexes in the mouse heart. We report that compared to dystrophin, μDys has altered associations with α1- and β2-syntrophins, as well as cavins, a group of caveolae-associated signaling proteins. In particular, we found that membrane localization of cavin-1 and cavin-4 in cardiomyocytes requires dystrophin and is profoundly disrupted in the heart of mdx5cv mice, a model of DMD. Following cardiac stress/damage, membrane-associated cavin-4 recruits the signaling molecule ERK to caveolae, which activates key cardio-protective responses. Evaluation of ERK signaling revealed a profound inhibition, below physiological baseline, in the mdx5cv mouse heart. Expression of μDys in mdx5cv mice prevented the development of cardiac histopathology but did not rescue membrane localization of cavins nor did it normalize ERK signaling. Our study provides the first comparative analysis of purified protein complexes assembled in vivo by full-length dystrophin and a therapeutic micro-dystrophin construct. This has revealed disruptions in cavins and ERK signaling that may contribute to DMD cardiomyopathy. This new knowledge is important for ongoing efforts to prevent and treat heart disease in DMD patients.

Mouse models of sarcopenia: classification and evaluation.

Sarcopenia is a progressive and widespread skeletal muscle disease that is related to an increased possibility of adverse consequences such as falls, fractures, physical disabilities and death, and its risk increases with age. With the deepening of the understanding of sarcopenia, the disease has become a major clinical disease of the elderly and a key challenge of healthy ageing. However, the exact molecular mechanism of this disease is still unclear, and the selection of treatment strategies and the evaluation of its effect are not the same. Most importantly, the early symptoms of this disease are not obvious and are easy to ignore. In addition, the clinical manifestations of each patient are not exactly the same, which makes it difficult to effectively study the progression of sarcopenia. Therefore, it is necessary to develop and use animal models to understand the pathophysiology of sarcopenia and develop therapeutic strategies. This paper reviews the mouse models that can be used in the study of sarcopenia, including ageing models, genetically engineered models, hindlimb suspension models, chemical induction models, denervation models, and immobilization models; analyses their advantages and disadvantages and application scope; and finally summarizes the evaluation of sarcopenia in mouse models.

Two Isoforms of Eya3 Influence Muscle Cell Differentiation and Become Dysregulated in Striated Muscle Diseases

Alternative splicing is a ubiquitous gene regulatory mechanism by which diverse transcripts are derived from a finite genome. During development, complex splicing transitions occur, leading to varied transcript profiles in fetal and adult tissues. Like gene expression, splicing often becomes dysregulated in cancer, neurological, and muscular diseases. One barrier to therapeutic targeting of alternative splicing is that the function of splice isoforms, both physiologically and pathologically, are vastly understudied. Here, we begin to address this knowledge gap by describing an evolutionarily conserved alternative splicing event in eyes absent homolog 3 (Eya3) gene for the first time. The short isoform of Eya3 is a dual threonine- and tyrosine-phosphatase that is known to promote cell growth and chemotherapeutic resistance. By analyzing RNA-sequencing data from various mouse tissues, we identified the long isoform of Eya3, which contains an additional 138nt, representing a 46 amino acid in-frame insertion immediately following the threonine phosphatase domain. Using reverse transcription-PCR (RT-PCR) of mouse, human, and rabbit tissues, we discovered that Eya3 splicing is tissue-specific, with the long isoform expressed exclusively in the heart, skeletal muscle, and brain. Additionally, we found that during heart and skeletal muscle development, expression of the long Eya3 isoform gradually increases relative to the expression of the short isoform. In myotonic dystrophy type 1 patient hearts, and failing mouse hearts, the short Eya3 isoform is re-expressed, illustrating that Eya3 splicing is dysregulated in striated muscle diseases. To understand Eya3 splicing in further molecular detail, we utilized the well-established C2C12 murine myoblast cell line. Differentiation of myoblasts to myotubes robustly recapitulates the Eya3 splicing transition observed during tissue development, making them an appropriate cell culture system for our work. Depletion of Eya3 via siRNA transfection inhibited myoblast proliferation and fusion. Interestingly, blocking the endogenous Eya3 alternative splicing transition with morpholino antisense oligonucleotides also suppressed normal differentiation as determined by immunohistochemical staining and confocal microscopy. These results indicate that Eya3, and its splice isoforms, play an important role in early muscle development. In summary, our studies uncover a developmentally-regulated, tissue-specific, and disease-relevant splicing event in Eya3. Moving forward, we seek to determine the molecular mechanism by which Eya3 isoforms regulate normal muscle development and to evaluate Eya3 as a potential therapeutic target.

Myosin: Structure, Function, Regulation and Disease

The human myosin heavy chain superfamily comprises 12 different classes. Class 2 is the largest and is made up of 14 myosin heavy chain (MHC) genes (and 1 pseudogene). Class 2 myosin heavy chains form a dimer of two heavy chains, and associate with 2 pairs of light chains (essential and regulatory). Of the 13 types of class 2 myosins, 10 are expressed in striated muscle and the remaining 4 in non-muscle cells and smooth muscle. All of the class 2 myosins form filaments. In striated muscle, the filaments contain precisely 294 molecules. In contrast, non-muscle myosins form much shorter filaments (about 30 molecules). The activity of all of these myosins is regulated by an interaction of the heads (comprising the motor domain and lever) with the first part of the coiled coil (subfragment 2, S2) to form the so-called ‘interacting heads’ motif. Non-muscle and smooth muscle myosin heads are additionally regulated by an interaction of the head with the tail forming region (light meromyosin, LMM) to form a shutdown molecule. We use a combination of cell biology, and structural approaches, including electron microscopy to understand the effects of disease-causing mutations in S2 and in LMM in class 2 myosins. Mutations in striated myosins (MyHCβ, MyHC2a) cause cardiac and skeletal muscle diseases respectively, although mutations in the distal LMM region of MyHCβ are predominantly associated with skeletal muscle disease. Mutations in non-muscle myosin 2A (NM2A) cause a range of bleeding disorders. We determine how specific mutations affect the myosin's ability to form filaments and how they affect formation of its shutdown state. For example, we use circular dichroism to determine if specific mutations affect the secondary structure of LMM. We use negative stain electron microscopy to evaluate filament formation by the LMM (fused to GST, to prevent paracrystal formation) and we use GFP-tagged MHC to evaluate the ability of each mutant to incorporate into filaments in cultured cells, myotubes and adult rat cardiomyocytes (Parker et al. (2018) J. Mol. Biol). We recently solved the structure of full-length smooth muscle myosin (SMM) in its shutdown state (Scarff et al.. (2020) Nature) using CryoEM. This shows how the shutdown state is stabilised and enables us to predict how mutations might disrupt it. Together with additional structural studies, we are starting to understand how specific mutations affect myosin function, to gain a better understanding of the disease process. Support or Funding Information This research is supported by the Medical Research Council, MR/R009406/1 and MR/S023593/1 to MP.

MYH7-related disorders in two Bulgarian families: Novel variants in the same region associated with different clinical manifestation and disease penetrance

Pathogenic variants in MYH7 cause a wide range of cardiac and skeletal muscle diseases with childhood or adult onset. These include dilated and/or hypertrophic cardiomyopathy, left ventricular non-compaction cardiomyopathy, congenital myopathies with multi-minicores and myofiber type disproportion, myosin storage myopathy, Laing distal myopathy and others (scapulo-peroneal or limb-girdle muscle forms). Here we report the results from molecular genetic analyses (NGS and Sanger sequencing) of 4 patients in two families with variable neuromuscular phenotypes with or without cardiac involvement. Interestingly, variants in MYH7 gene appeared to be the cause in all the cases. A novel nonsense variant c.5746C>T, p.(Gln1916Ter) was found in the patient in Family 1 who deceased at the age of 2 years 4 months with the clinical diagnosis of dilated cardiomyopathy, whose father died before the age of 40 years, due to cardiac failure with clinical diagnosis of suspected limb-girdle muscular dystrophy. A splice acceptor variant c.5560–2A>C in MYH7 was detected in the second proband and her sister, with late onset distal myopathy without cardiac involvement. These different phenotypes (muscular involvement with severe cardiomyopathy and pure late onset neuromuscular phenotype without heart involvement) may result from novel MYH7 variants, which most probably impact the LMM (light meromyosin) domain's function of the mature protein.

Bidirectional interconversion between PtdIns4P and PtdIns(4,5)P2 is required for autophagic lysosome reformation and protection from skeletal muscle disease

ABSTRACT Autophagic lysosome reformation (ALR) recycles autolysosome membranes formed during autophagy, to make lysosomes and is essential for continued autophagy function. Localized membrane remodeling on autolysosomes leads to the extension of reformation tubules, which undergo scission to form new lysosomes. The phosphoinositides phosphatidylinositol-4-phosphate (PtdIns4P) and phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P2) induce this remodeling by recruiting protein effectors to membranes. We identified the inositol polyphosphate 5-phosphatase INPP5K, which converts PtdIns(4,5)P2 to PtdIns4P is essential for ALR in skeletal muscle. INPP5K mutations that reduce its 5-phosphatase activity are known to cause muscular dystrophy, via an undefined mechanism. We generated skeletal muscle-specific inpp5k knockout mice which exhibited severe muscle disease, with lysosome depletion and marked autophagy inhibition. This was due to decreased PtdIns4P and increased PtdIns(4,5)P2 on autolysosomes, causing reduced scission of reformation tubules. ALR was restored in cells with loss of INPP5K by expression of wild-type INPP5K, but not muscle-disease causing mutants. Therefore on autolysosomes, both PtdIns(4,5)P2 generation and its removal by INPP5K is required for completion of ALR. Furthermore, skeletal muscle shows a dependence on the membrane recycling ALR pathway to maintain lysosome homeostasis and ensure the protective role of autophagy against disease.

Mutations Q93H and E97K in TPM2 Disrupt Ca-Dependent Regulation of Actin Filaments.

Tropomyosin is a two-chain coiled coil protein, which together with the troponin complex controls interactions of actin with myosin in a Ca2+-dependent manner. In fast skeletal muscle, the contractile actin filaments are regulated by tropomyosin isoforms Tpm1.1 and Tpm2.2, which form homo- and heterodimers. Mutations in the TPM2 gene encoding isoform Tpm2.2 are linked to distal arthrogryposis and congenital myopathy—skeletal muscle diseases characterized by hyper- and hypocontractile phenotypes, respectively. In this work, in vitro functional assays were used to elucidate the molecular mechanisms of mutations Q93H and E97K in TPM2. Both mutations tended to decrease actin affinity of homo-and heterodimers in the absence and presence of troponin and Ca2+, although the effect of Q93H was stronger. Changes in susceptibility of tropomyosin to trypsin digestion suggested that the mutations diversified dynamics of tropomyosin homo- and heterodimers on the filament. The presence of Q93H in homo- and heterodimers strongly decreased activation of the actomyosin ATPase and reduced sensitivity of the thin filament to [Ca2+]. In contrast, the presence of E97K caused hyperactivation of the ATPase and increased sensitivity to [Ca2+]. In conclusion, the hypo- and hypercontractile phenotypes associated with mutations Q93H and E97K in Tpm2.2 are caused by defects in Ca2+-dependent regulation of actin–myosin interactions.

Characterization of hiPSC-Derived Muscle Progenitors Reveals Distinctive Markers for Myogenic Cell Purification Toward Cell Therapy.

SummaryThe transplantation of muscle progenitor cells (MuPCs) differentiated from human induced pluripotent stem cells (hiPSCs) is a promising approach for treating skeletal muscle diseases such as Duchenne muscular dystrophy (DMD). However, proper purification of the MuPCs before transplantation is essential for clinical application. Here, by using MYF5 hiPSC reporter lines, we identified two markers for myogenic cell purification: CDH13, which purified most of the myogenic cells, and FGFR4, which purified a subset of MuPCs. Cells purified with each of the markers showed high efficiency for regeneration after transplantation and contributed to the restoration of dystrophin expression in DMD-immunodeficient model mice. Moreover, we found that MYF5 regulates CDH13 expression by binding to the promoter regions. These findings suggest that FGFR4 and CDH13 are strong candidates for the purification of hiPSC-derived MuPCs for therapeutical application.

AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1.

Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.

HnRNP L is essential for myogenic differentiation and modulates myotonic dystrophy pathologies

RNA-binding proteins (RBPs) play an important role in skeletal muscle development and disease by regulating RNA splicing. In myotonic dystrophy type 1 (DM1), the RBP MBNL1 (muscleblind-like) is sequestered by toxic CUG repeats, leading to missplicing of MBNL1 targets. Mounting evidence from the literature has implicated other factors in the pathogenesis of DM1. Herein we sought to evaluate the functional role of the splicing factor hnRNP L in normal and DM1 muscle cells. Co-immunoprecipitation assays using hnRNPL and MBNL1 expression constructs and splicing profiling in normal and DM1 muscle cell lines were performed. Zebrafish morpholinos targeting hnrpl and hnrnpl2 were injected into one-cell zebrafish for developmental and muscle analysis. In human myoblasts downregulation of hnRNP L was achieved with shRNAi. Ascochlorin administration to DM1 myoblasts was performed and expression of the CUG repeats, DM1 splicing biomarkers, and hnRNP L expression levels were evaluated. Using DM1 patient myoblast cell lines we observed the formation of abnormal hnRNP L nuclear foci within and outside the expanded CUG repeats, suggesting a role for this factor in DM1 pathology. We showed that the antiviral and antitumorigenic isoprenoid compound ascochlorin increased MBNL1 and hnRNP L expression levels. Drug treatment of DM1 muscle cells with ascochlorin partially rescued missplicing of established early biomarkers of DM1 and improved the defective myotube formation displayed by DM1 muscle cells. Together, these studies revealed that hnRNP L can modulate DM1 pathologies and is a potential therapeutic target.

A lamin A/C variant causing striated muscle disease provides insights into filament organization

The LMNA gene encodes the A-type lamins, which polymerize into ∼3.5-nm-thick filaments and, together with B-type lamins and associated proteins, form the nuclear lamina. Mutations in LMNA cause a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts from Lmna H222P/H222P mice, which develop cardiomyopathy and muscular dystrophy. Although the organization of the lamina appeared unaltered, there were changes in chromatin and B-type lamin expression. An increase in nuclear size and consequently a relative reduction in heterochromatin near the lamina allowed for a higher resolution structural analysis of lamin filaments using cryo-electron tomography. This was most apparent when visualizing lamin filaments in situ and using a nuclear extraction protocol. Averaging of individual segments of filaments in Lmna H222P/H222P mouse fibroblasts resolved two polymers that constitute the mature filaments. Our findings provide better views of the organization of lamin filaments and the effect of a striated muscle disease-causing mutation on nuclear structure.

Longitudinal study of MRI and functional outcome measures in facioscapulohumeral muscular dystrophy

BackgroundFacioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function.MethodsWe studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures.ResultsThere was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced.ConclusionsAssessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.

Torpor versus interbout arousal: what is more important for protein metabolism and regeneration?

Hibernation is used by specie as diverse as ground squirrels, snakes and bats to cope with reduced food availability and lowered temperatures and is a unique model for studying the molecular mechanisms of plasticity in striated muscles. Important questions in modern muscle biology are why some skeletal muscles atrophy and other muscles such as the diaphragm and the heart hypertrophy during hibernation, and why, despite the atrophy, skeletal muscle strength and fatigue resistance are maintained after arousal. The molecular mechanisms responsible are of interest both from a fundamental biological viewpoint and as a potential therapy for patients in critical care units. In this issue of Experimental Physiology, Yan et al. (2021) shed light on the distinctive features of the molecular mechanisms involved in the development of the hypertrophic response in the diaphragm and the atrophic response in the gastrocnemius muscle in hibernating Daurian ground squirrels. In particular, the authors showed that a decrease in protein synthesis, an increase in protein degradation and a decrease in muscle regeneration potential contributed to the atrophy of the gastrocnemius muscles during torpor, while an increase in protein synthesis, a decrease in protein degradation and an increase in muscle regeneration potential contributed to diaphragm muscle hypertrophy. In discussing these new and interesting results, it can be assumed, however, that a significant contribution to the formation of hypertrophic or atrophic muscle phenotype could have been made by changes in anabolic and catabolic processes occurring in interbout arousals, as indicated by the results of recent studies (Chang et al., 2020; Popova et al., 2020 ). Further research is needed to show how important interbout arousals are in the regulation of protein turnover and regeneration in different striated muscles in hibernating animals. Understanding these and other molecular mechanisms is important for choosing strategies and methods for treatment of skeletal muscle pathologies and diseases of the cardiovascular system, as well as for avoiding injurious interventions in cases of energy deficits in critical illness (Stanzani et al., 2020). None declared.