Editor’s Choice Articles

Pleural mesothelioma (PM) is a tumor related to adverse prognosis. The PM WHO classification has mainly identified three major subtypes of PM which are epithelioid, biphasic, and sarcomatoid. Sarcopenia is a medical issue related to a reduction in muscle mass and strength. It represents a major health issue globally because it is related to adverse effects such as hospitalization, increased length of stay, disability, increased morbidity and mortality and augmented health care expenditures. In this literature review, we attempted to examine the upcoming association between sarcopenia and PM. As recorded by the current literature, muscle loss in PM subjects was related to poorer survival and lower levels of activity. Subjects with PM had increased rates of pre-sarcopenia and malnutrition, while pre-sarcopenia was related to worse activity levels, and malnutrition was related to worse quality of life (QoL). Both tumor volume and sarcopenia were related to long-term mortality in surgically treated PM subjects, while sarcopenia was present both pre-operatively and post-operatively in these subjects. In addition, post-operative sarcopenic subjects showed a decreased 3-year overall survival (OS) in comparison with those who did not have sarcopenia, while pre-operative sarcopenia was importantly related to an increased rate of post-operative adverse outcomes. More studies are needed to validate these claims. Full article

Eculizumab is a monoclonal antibody blocking the terminal complement protein C5. As demonstrated in the phase III randomized, placebo-controlled, REGAIN clinical trial, eculizumab is efficacious in acetylcholine receptor antibody (AChR-Ab)-positive refractory generalized myasthenia gravis (gMG) (Myasthenia Gravis Foundation of America—MGFA class II–IV). It has not been studied in severe myasthenic exacerbation or myasthenic crisis (MGFA V). A 73-year-old man diagnosed with myasthenia gravis AChR-Ab positivity came to our observation for symptoms of bulbar and ocular weakness and unresponsiveness or intolerability to conventional immunosuppressive therapies (prednisone and azathioprine). Due to the recurrent clinical worsening with intubation over a short-term period, the patient was treated with eculizumab. After 15 days of eculizumab treatment, we observed a significant recovery of clinical condition. We discharged the patient to an outpatient regimen, where he is continuing with maintenance doses of eculizumab and slowly tapering steroid intake. The use of eculizumab in myasthenic crises is still anecdotal. Our case aims to provide eculizumab benefit for refractory severe gMG in a practical, real-world setting beyond the criteria of the REGAIN study. Further studies are needed to evaluate the efficacy and safety of eculizumab in myasthenic crises. Full article

The use of electromyographic biofeedback (EMG-BF) in the rehabilitation of injuries has been widely referenced in the psychological literature. However, despite some pioneering work in the field of sports, its use in the rehabilitation of sports injuries has hardly been explored. A case of two professional soccer players who each suffered a distal radius fracture is presented here. Parallel to the rehabilitation plan established by medical services, an intervention strategy using EMG-BF was established. An EMG-BF intervention was performed on the brachioradialis muscle with the aim of improving the voluntary control of its electromyographic activity. The study protocol was registered with the identifier NCT05376072. An ABA design was used. In each session, a pre- and postline was recorded to determine the EMG gain acquired at each point of the session. After six sessions, the intervention was terminated. One more follow-up session was performed. The results obtained indicated the efficacy of the intervention; a statistically significant increase in muscle activity in the brachioradialis muscle was observed. Full article

This study evaluated muscle composition, quality, and strength of non-weight bearing and weight bearing muscles between males and females. Twenty-eight, healthy males (n = 14; mean ± SD; age = 25.1 ± 4.2 years; height = 181.9 ± 10.6 cm; weight = 91.6 ± 17.2 kg) and females (n = 14; age = 25.0 ± 3.4 years; height = 165.9 ± 6.9 cm; weight = 66.0 ± 10.2 kg) underwent body composition assessment to estimate body fat (%BF) and total-body, arm, and leg fat-free mass (TFFM, ArmFFM, and LegFFM, respectively) and muscle composition via B-mode ultrasound to measure muscle cross-sectional area (mCSA), echo intensity (EI), and thickness (mT) of four muscles [rectus femoris (RF), vastus lateralis (VL), flexor digitorum superficialis (FDS), and flexor carpi radialis (FCR)]. Additionally, upper- [handgrip strength (HG)] and lower-body [leg extension (LE)] maximal strength were measured, recorded, and expressed relative to FFM to determine muscle quality (MQ) for the dominant arm and leg, respectively. Males had greater TFFM, ArmFFM, and LegFFM (p < 0.001), mCSA for RF, VL, FCR, and FDS (p < 0.001), and mT for RF, VL (p < 0.001–0.006). Females had greater EI for RF, VL, and FDS (p = 0.003–0.01). Negative correlations were identified between EI and MQ for all muscles in males and females, however, no significance was determined. Despite the sex differences in absolute strength and size, muscle quality (relative strength) was not different for the upper nor lower body. Full article

Skeletal muscle MRI studies in limb-girdle muscular dystrophy (LGMD) have increased over the past decades, improving the utility of MRI as a differential diagnostic tool. Nevertheless, the relative rarity of individual genotypes limits the scope of what each study can address, making it challenging to obtain a comprehensive overview of the MRI image of this splintered group. Furthermore, MRI studies have varied in their methods for assessing fat infiltration, which is essential in skeletal muscle MRI evaluation. It stayed problematic and impeded attempts to integrate multiple studies to cover the core MRI features of a distinct LGMD. In this study, we conducted a systematic review of LGMD in adults published until April 2023; 935 references were screened in PubMed and EMBASE, searches of the gray literature, and additional records were added during the screening process. Finally, 39 studies were included in our final analysis. We attempted to quantitatively synthesize the MRI data sets from the 39 individual studies. Finally, we illustrated ideal and simple MRI muscle involvement patterns of six representative LGMD genotypes. Our summary synthesis reveals a distinct distribution pattern of affected muscles by LGMD genotypes, which may be helpful for a quick first-tier differential diagnosis guiding genetic diagnostics. Full article

Electromyographic biofeedback (EMG-BF) is a technique that can contribute to the improvement of muscle tone and control in the rehabilitation process after injury. The aim of this research was to determine the effectiveness of EMG-BF in increasing the electromyographic activity of the vastus lateralis after knee injury. The sample consisted of four individuals who had undergone surgery or rehabilitation to resolve either a partial meniscal tear or a patellar tendon strain. The intervention consisted of a program of ten sessions of EMG-BF work. Twelve trials were performed in each session, in which participants were instructed to target the muscle tension produced by the vastus lateralis of the uninjured hemilateral limb. Of the twelve trials in each session, the first three and the last three were performed without feedback, and the intermediate six with feedback. The recording of muscle activity was performed using CY-351/2 Mioback equipment, which allowed the amplitude of the electromyographic signal to be evaluated. The results indicated that the sample analyzed reached greater amplitude during the biofeedback trials, both for the maximum (Z = −13.43, p < 0.001, Cohen’s d = 0.64, 95% CI (0.27, 1.01)) and mean (Z = −7.26, p < 0.001, Cohen’s d = 0.24, 95% CI (−0.12, 0.60)) values. The amplitude also increased throughout the ten sessions, both for the maximum (Z = −3.06, p < 0.01, Cohen’s d = 1.37, 95% CI (0.29, 2.45)) and mean (Z = −3.06, p < 0.01, Cohen’s d = 1.20, 95% CI (0.34, 2.08)) values. Thus, the results highlight the efficacy of this technique in improving muscle activity, suggesting that it is a useful therapeutic procedure in injury recovery. Full article

The heart is composed of muscle cells called cardiomyocytes, including a specialized population named pacemaker cells that form the cardiac conduction system (CCS), which is responsible for generating the action potential dictating heart contractions. Failure of the CCS system leads to cardiac arrhythmias, which require complicated therapies and often the surgical implantation of electrical pacemakers. However, recent research has focused on the development of novel therapies using biological pacemakers that aim to substitute electrical devices. While most signaling pathways and transcription factors involved in the development of the pacemaker cells are known, the upstream regulatory networks need to be predicted through computer-based databases, mathematical modeling, as well as the functional testing of the regulatory elements in vivo, indicating the need for further research. Here, we summarize the current knowledge about the vertebrate myocardial CCS system and the development of the pacemaker cells, as well as emphasize the areas of future research to clarify the regulation of muscle pacemaker cells and the ease of development of biological therapies. Full article

Skeletal muscle is a complex tissue comprising multinucleated and post-mitotic cells (i.e., myofibers). Given this, skeletal muscle must maintain a fine balance between growth and degradative signals. A major system regulating the remodeling of skeletal muscle is autophagy, where cellular quality control is mediated by the degradation of damaged cellular components. The accumulation of damaged cellular material can result in elevated apoptotic signaling, which is particularly relevant in skeletal muscle given its post-mitotic nature. Luckily, skeletal muscle possesses the unique ability to regenerate in response to injury. It is unknown whether a relationship between autophagy and apoptotic signaling exists in injured skeletal muscle and how autophagy deficiency influences myofiber apoptosis and regeneration. In the present study, we demonstrate that an initial inducible muscle-specific autophagy deficiency does not alter apoptotic signaling following cardiotoxin injury. This finding is presumably due to the re-establishment of ATG7 levels following injury, which may be attributed to the contribution of a functional Atg7 gene from satellite cells. Furthermore, the re-expression of ATG7 resulted in virtually identical regenerative potential. Overall, our data demonstrate that catastrophic injury may “reset” muscle gene expression via the incorporation of nuclei from satellite cells. Full article

The present study is the first research that analyzes the quality of life (QoL) of people affected by a dominant form of limb–girdle muscular dystrophy, specifically limb–girdle muscular dystrophy D2 (LGMD-D2). Additionally, clinical forms of the individual cases of the six affected patients are presented. This study also aims to explore the differences between patients’ reports and caregivers’ reports, and between LGMD-D2 and recessive forms of LGMD. The instruments used were as follows: sociodemographic data, GSGC, and INQoL instrument. The sample consisted of six people affected by LGMD-D2: three caregivers of three affected people, and three patients with recessive LGMD. They came from associations of affected people and a hospital in Padua. Those affected have multiple symptoms that lead to disability, which ultimately leads to dependence on the assistance. The present study shows that LGMD-D2 has a greater impact on activities of daily living, fatigue, muscle pain, and independence than other LGMD pathologies or other neuromuscular diseases. It also appears that age could influence QoL, and that muscle weakness is a very disabling symptom in this variant. In the current context of constantly developing research for new treatments, it is essential to analyze which aspects are most affected. Finally, caregivers can play an essential role in symptom reporting, as certain psychological adjustment mechanisms in the patient may be interfering with the objectivity of the report. Full article

Background: Falls risk assessment tools are used in hospital inpatient settings to identify patients at increased risk of falls to guide and target interventions for fall prevention. In 2022, Western Health, Melbourne, Australia, introduced a new falls risk assessment tool, the Western Health St. Thomas’ Risk Assessment Tool (WH-STRATIFY), which adapted The Northern Hospital’s risk tool (TNH-STRATIFY) by adding non-English speaking background and falls-risk medication domains to reflect patient demographics. WH-STRATIFY replaced Peninsula Health Risk Screening Tool (PH-FRAT) previously in use at Western Health. This study compared the predictive accuracy of the three falls risk assessment tools in an older inpatient high-risk population. Aims: To determine the predictive accuracy of three falls risk assessment tools (PH-FRAT, TNH-STRATIFY, and WH-STRATIFY) on admission to Geriatric Evaluation Management (GEM) units (subacute inpatient wards where the most frail and older patients rehabilitate under a multi-disciplinary team). Method: A retrospective observational study was conducted on four GEM units. Data was collected on 54 consecutive patients who fell during admission and 62 randomly sampled patients who did not fall between December 2020 and June 2021. Participants were scored against three falls risk assessment tools. The event rate Youden (Youden Index^ER) indices were calculated and compared using default and optimal cut points to determine which tool was most accurate for predicting falls. Results: Overall, all tools had low predictive accuracy for falls. Using default cut points to compare falls assessment tools, TNH-STRATIFY had the highest predictive accuracy (Youden Index^ER = 0.20, 95% confidence interval CI = 0.07, 0.34). The PH-FRAT (Youden Index^ER = 0.01 and 95% CI = −0.04, 0.05) and WH-STRATIFY (Youden Index^ER = 0.00 and 95% CI = −0.04, 0.03) were statistically equivalent and not predictive of falls compared to TNH-STRATIFY. When calculated optimal cut points were applied, predictive accuracy improved for PH-FRAT (Cut point 17, Youden Index^ER = 0.14 and 95% CI = 0.01, 0.29) and WH-STRATIFY (Cut point 7, Youden Index^ER = 0.18 and 95% CI = 0.00, 0.35). Conclusions: TNH-STRATIFY had the highest predictive accuracy for falls. The predictive accuracy of WH-STRATIFY improved and was significant when the calculated optimal cut point was applied. The optimal cut points of falls risk assessment tools should be determined and validated in different clinical settings to optimise local predictive accuracy, enabling targeted fall risk mitigation strategies and resource allocation. Full article

This study aimed to examine the chronic effect of a stair climbing–descending exercise (ST-EX) program on glycemic control in individuals with type 2 diabetes (T2D). Sixteen T2D participants were randomly divided into two groups and followed up over 12 weeks: they either performed regular ST-EX after meals at home (n = 8) or maintained their daily routine (CON; no training) (n = 8). The participants in the ST-EX group were instructed to perform a minimum of 12 sessions/week of ST-EX for more than three days/week. One session of ST-EX consisted of two repetitions of 3 min bouts of climbing to the second floor, followed by walking down to the first floor. Fourteen participants completed the study (seven for each group). The decrease in glycoalbumin levels was significantly greater in the ST-EX group (mean value: −1.0%) than in the CON group (+0.4%). Moreover, the knee extension force increased greatly in the ST-EX group (+0.2 Nm/kg) compared with that in the CON group (−0.1 Nm/kg), with no significant change in the skeletal muscle mass. Performing regular ST-EX after meals may be an effective strategy to improve glycemic control and lower-extremity muscle strength in individuals with T2D. Full article

The skeletal muscle is a highly plastic tissue that shows a remarkable adaptive capacity in response to acute and resistance exercise, and modifies its composition to adapt to use and disuse, a process referred to as muscle plasticity. Heat shock proteins (HSPs), a class of evolutionarily conserved molecular chaperones, have been implicated in the regulation of skeletal muscle plasticity. Here, we summarize key findings supporting the notion that HSPs are important components required to maintain skeletal muscle integrity and functionality. HSPs participate in the transcriptional program required for myogenesis and are activated following muscle exercise and injury. Their dysfunction, either as a consequence of improper expression or genetic mutations, contributes to muscle atrophy and leads to the development of myopathies and peripheral motor neuropathies. Denervation/reinnervation and repeated rounds of nerve degeneration/regeneration have been observed in motor neuropathies, suggesting that an imbalance in HSP expression and function may impair the repair of the neuromuscular junctions. Boosting HSP activity may help preventing muscle atrophy by promoting muscle differentiation and helping the repair of NMJs. Boosting HSP function may also help to combat the development of rhabdomyosarcoma (RMS), a highly aggressive type of pediatric soft tissue sarcoma whose cells have skeletal muscle features but are unable to fully differentiate into skeletal muscle cells. Full article

Musculoskeletal health is directly linked to independence and longevity, but disease and aging impairs muscle mass and health. Complete repair after a pathological or physiological muscle injury is critical for maintaining muscle function, yet muscle repair is compromised after disuse, or in conditions such as metabolic diseases, cancer, and aging. Regeneration of damaged tissue is critically dependent upon achieving the optimal function of satellite cells (muscle stem cells, MSCs). MSC remodeling in muscle repair is highly dependent upon its microenvironment, and metabolic health of MSCs, which is dependent on the functional capacity of their mitochondria. Muscle repair is energy demanding and mitochondria provide the primary source for energy production during regeneration. However, disease and aging induce mitochondrial dysfunction, which limits energy production during muscle regeneration. Nevertheless, the role of mitochondria in muscle repair likely extends beyond the production of ATP and mitochondria could provide potentially important regulatory signaling to MSCs during repair from injury. The scope of current research in muscle regeneration extends from molecules to exosomes, largely with the goal of understanding ways to improve MSC function. This review focuses on the role of mitochondria in skeletal muscle myogenesis/regeneration and repair. A therapeutic strategy for improving muscle mitochondrial number and health will be discussed as a means for enhancing muscle regeneration. Highlights: (a). Mitochondrial dysfunction limits muscle regeneration; (b). Muscle stem cell (MSC) function can be modulated by mitochondria; (c). Enhancing mitochondria in MSCs may provide a strategy for improving muscle regeneration after an injury. Full article

Skeletal muscle physiology is regulated by microRNA that are localized within skeletal muscle (myomiRs). This study investigated how the expression of myomiRs and genes regulating skeletal muscle mass and myogenesis are influenced in response to acute and consecutive days of exercise-related signaling using the exercise mimetic, formoterol, in vitro. Human skeletal muscle cells were proliferated and differentiated for 6 days. Experimental conditions included: (a) control, (b) acute formoterol stimulation (AFS), and (c) consecutive days of formoterol stimulation (CFS). For AFS, myotubes were treated with 30 nM of formoterol for three hours on day 6 of differentiation, and this was immediately followed by RNA extraction. For CFS, myotubes were treated with 30 nM of formoterol for three hours on two or three consecutive days, with RNA extracted immediately following the final three-hour formoterol treatment. We observed increased myomiR expression for both AFS and CFS. AFS appeared to promote myogenesis, but this effect was lost with CFS. Additionally, we observed increased expression of genes involved in metabolism, mitochondrial biogenesis, and muscle protein degradation in response to AFS. myomiR and gene expression appear to be sensitive to acute and long-term exercise-related stimuli, and this likely contributes to the regulation of skeletal muscle mass. Full article

Amyotrophic lateral sclerosis (ALS) is a complex systemic disease that primarily involves motor neuron dysfunction and skeletal muscle atrophy. One commonly used mouse model to study ALS was generated by transgenic expression of a mutant form of human superoxide dismutase 1 (SOD1) gene harboring a single amino acid substitution of glycine to alanine at codon 93 (G93A*SOD1). Although mutant-SOD1 is ubiquitously expressed in G93A*SOD1 mice, a detailed analysis of the skeletal muscle expression pattern of the mutant protein and the resultant muscle pathology were never performed. Using different skeletal muscles isolated from G93A*SOD1 mice, we extensively characterized the pathological sequelae of histological, molecular, ultrastructural, and biochemical alterations. Muscle atrophy in G93A*SOD1 mice was associated with increased and differential expression of mutant-SOD1 across myofibers and increased MuRF1 protein level. In addition, high collagen deposition and myopathic changes sections accompanied the reduced muscle strength in the G93A*SOD1 mice. Furthermore, all the muscles in G93A*SOD1 mice showed altered protein levels associated with different signaling pathways, including inflammation, mitochondrial membrane transport, mitochondrial lipid uptake, and antioxidant enzymes. In addition, the mutant-SOD1 protein was found in the mitochondrial fraction in the muscles from G93A*SOD1 mice, which was accompanied by vacuolized and abnormal mitochondria, altered OXPHOS and PDH complex protein levels, and defects in mitochondrial respiration. Overall, we reported the pathological sequelae observed in the skeletal muscles of G93A*SOD1 mice resulting from the whole-body mutant-SOD1 protein expression. Full article

It is well known that muscular dystrophy disease severity is controlled by genetic modifiers. The expectation is that by identifying these modifiers, we can illuminate additional therapeutic targets with which to combat the disease. To this end we have been investigating the MRL mouse strain, which is highly resistant to muscular dystrophy-mediated fibrosis. The MRL mouse strain contains two mitochondrial-encoded, naturally occurring heteroplasmies: T3900C in tRNA-Met, and variable adenine insertions at 9821 in tRNA-Arg. Heteroplasmies are mitochondrial mutations that are variably present in a cell’s mitochondria. Therefore, MRL cells can contain 0 to 100% of each mitochondrial mutation. We have chosen the severely affected ϒ-sarcoglycan (Sgcg–/–) deficient mice on the DBA2/J background as our muscular dystrophy model to demonstrate the effects of these mitochondrial heteroplasmies on disease severity. Mice from the (Sgcg–/–) DBA2/J (D) and wildtype MRL (M) strains were crossed for more than 10 generations to establish two separate, pure breeding mouse lines: Sgcg+/–Nuc^DMito^%M and Sgcg+/–Nuc^MMito^%M. The Sgcg–/– mice from these separate lines were analyzed at 8 weeks old for membrane permeability, hydroxyproline content, pAMPK content, fibronectin content, and percentage of each heteroplasmy. We have identified that the MRL mitochondrial mutation T3900C confers a portion of the fibrosis resistance identified in the MRL mouse strain. These results have been extended to significantly correlate increased MRL mitochondria with increased pAMPK and decreased muscular dystrophy fibrosis. The beneficial mechanisms controlled by the MRL mitochondria will be discussed. We are establishing metabolic aspects of muscular dystrophy pathogenesis. These metabolic pathways will now be investigated for therapeutic targets. Full article

Efficacy of obesity treatments varies between individuals, highlighting the presence of responders and non-responders. Whilst exercise alone or exercise combined with diet leads to underwhelming weight loss for most, there exist super responders losing significant weight. Furthermore, in response to weight loss, the majority but not all patients tend to regain weight. Within the biopsychosocial model, biology as a determinant of response has been underappreciated. The understanding of the role that organs beyond adipose tissue and the gastrointestinal tract play in appetite control and body weight regulation has developed in recent years. The aim of this review is to highlight potential myokines that may be important in appetite physiology and overall energy balance. A number of attractive targets are described that warrant further investigation. A deeper understanding of how these myokines may drive feeding behaviours has the potential to improve measures to prevent and treat obesity through a precision medicine approach. Full article