Limb Skeletal Muscle Research Articles

Low skeletal muscle mass as an early sign in children with fabry disease

Background & aimsFabry disease (FD) is a rare X-linked metabolic storage disorder due to the deficiency of lysosomal α-galactosidase A which causes the accumulation of glycosphingolipids throughout the body. Underweight and low BMI have been occasionally reported in FD patients previously. Whether underweight is common in the early stage of FD and body composition analysis to determine the cause have not been reported.MethodsChildren who were diagnosed with FD in the Children’s Hospital of Zhejiang University School of Medicine from July 2014 to December 2022 were enrolled. Clinical data were obtained from medical records. Whole body dual energy X-ray absorptiometry scans (DXA) were used to assess body composition (fat mass, FM; fat free mass, FFM and bone mass) according to the International Society of Clinical Densitometry’s standard operating method. Whole body muscle mass was calculated as fat-free mass minus bone mass. Appendicular skeletal muscle mass (ASM) was calculated as the sum of the arm and the leg muscle mass. The FM, FFM, ULSM and LLSM indices were calculated by dividing the total FM, FFM, and upper and lower limb skeletal muscle mass (ULSM and LLSM) by the height squared.ResultsA total of eighteen children (14 boys and 4 girls) were enrolled. Thirteen boys had the classical phenotype, and five children (1 boy with the N215S mutation and 4 girls) had the late-onset phenotype. Seven children with the classical phenotype (53.8%) and two of the five children (40%) with the late-onset phenotype had abnormal BMIs. Sixteen of the eighteen children (88.9%) had a height in the normal range, suggesting that low BMI was mainly due to underweight. By DXA body composition analysis, the FMI was abnormal in 3 children (2 boys and 1 girl), and the FFMI was abnormal in 12 children (9 boys and 3 girls). For the classical phenotype, 2 of the 13 children (15.4%) had abnormal FMI values, while 10 (76.9%) had abnormal FFMI values. Eight patients (61.5%) with the classical phenotype had a significant reduction in muscle mass index, ASM index and LLSM index values compared with age- and sex- matched Chinese controls. Late-onset patients also had mild low skeletal muscle mass compared to controls. The results suggested that low skeletal muscle mass is common in early FD.ConclusionsThis is the first study to examine body composition and muscle mass in early Fabry disease patients. Low skeletal muscle mass is a common early symptom in children with Fabry disease, suggesting that skeletal muscle is significantly affected in the early stages of FD.

Age-related gene expression signatures from limb skeletal muscles and the diaphragm in mice and rats reveal common and species-specific changes

BackgroundAs a result of aging, skeletal muscle undergoes atrophy and a decrease in function. This age-related skeletal muscle weakness is known as “sarcopenia”. Sarcopenia is part of the frailty observed in humans. In order to discover treatments for sarcopenia, it is necessary to determine appropriate preclinical models and the genes and signaling pathways that change with age in these models.Methods and resultsTo understand the changes in gene expression that occur as a result of aging in skeletal muscles, we generated a multi-time-point gene expression signature throughout the lifespan of mice and rats, as these are the most commonly used species in preclinical research and intervention testing. Gastrocnemius, tibialis anterior, soleus, and diaphragm muscles from male and female C57Bl/6J mice and male Sprague Dawley rats were analyzed at ages 6, 12, 18, 21, 24, and 27 months, plus an additional 9-month group was used for rats. More age-related genes were identified in rat skeletal muscles compared with mice; this was consistent with the finding that rat muscles undergo more robust age-related decline in mass. In both species, pathways associated with innate immunity and inflammation linearly increased with age. Pathways linked with extracellular matrix remodeling were also universally downregulated. Interestingly, late downregulated pathways were exclusively found in the rat limb muscles and these were linked to metabolism and mitochondrial respiration; this was not seen in the mouse.ConclusionsThis extensive, side-by-side transcriptomic profiling shows that the skeletal muscle in rats is impacted more by aging compared with mice, and the pattern of decline in the rat may be more representative of the human. The observed changes point to potential therapeutic interventions to avoid age-related decline in skeletal muscle function.

Effect of Otago Exercise on Indicators of Sarcopenia in the Elderly

This study was conducted to determine the effect of Otago exercise intervention on muscle mass, muscle strength, and physical performance, which are diagnostic indicators of sarcopenia, in elderly individuals aged 65 or older. The final subjects included 6 individuals in the walking exercise group and 5 people in the Otago exercise group. Walking exercises were conducted 12 times a week for 22 minutes at a time and more than 80 steps per minute whereas the Otago exercise was conducted four times a week for 50 minutes, a total of 12 times under the supervision of a senior movement leader. After the intervention, a diagnostic evaluation of sarcopenia was performed, and before and after the intervention, the intergroup skeletal muscle mass (ASM), grip force (Hand Grip), and SPPB were compared. The three evaluation parameters are related to physical function and showed that after each exercise intervention, the Otago exercise group exhibited an increase in the limb skeletal muscle and the SMI. The walking exercise resulted in a decrease in muscle strength, but the Otago exercise group showed an increase in this metric. The SPPB score increased in the Otago movement group, but no statistically significant results were obtained. It was demonstrated that the Otago exercise positively affects the index of muscle loss in the elderly, and is potentially effective for preventing and managing sarcopenia.

Gαi2 regulates the adult myogenesis of masticatory muscle satellite cells

Although similar to trunk and limb skeletal muscles, masticatory muscles are believed as unique in both developmental origins and myogenesis. Gαi2 has been demonstrated to promote muscle hypertrophy and muscle satellite cell differentiation in limb muscles. However, the effect of Gαi2 on masticatory muscles is still unexplored. This study aimed to identify the role of Gαi2 in the proliferation and differentiation of masticatory muscle satellite cells, further exploring the metabolic mechanism of masticatory muscles. The proliferation rate, myotube size, fusion index of masticatory muscle satellite cells and Pax7, Myf5, MyoD, Tcf21 and Musculin expressions were significantly decreased by Gαi2 knockdown, while in cells infected with AdV4-Gαi2, the proliferation rate, myotube size, fusion index and Tbx1 expression were significantly increased. Masticatory muscle satellite cells also displayed phenotype transformation as Gαi2 changed. In addition, Gαi2 altered myosin heavy chain (MyHC) isoforms of myotubes with less MyHC-2A expression in siGαi2 group and more MyHC-slow expression in AdV4-Gαi2 group. In conclusion, Gαi2 could positively affect the adult myogenesis of masticatory muscle satellite cells and maintain the superiority of MyHC-slow. Masticatory muscle satellite cells may have their unique Gαi2-regulated myogenic transcriptional networks, although they may share some common characteristics with trunk and limb muscles.

Deformable image registration based on single or multi-atlas methods for automatic muscle segmentation and the generation of augmented imaging datasets.

Muscle segmentation is a process relied upon to gather medical image-based muscle characterisation, useful in directly assessing muscle volume and geometry, that can be used as inputs to musculoskeletal modelling pipelines. Manual or semi-automatic techniques are typically employed to segment the muscles and quantify their properties, but they require significant manual labour and incur operator repeatability issues. In this study an automatic process is presented, aiming to segment all lower limb muscles from Magnetic Resonance (MR) imaging data simultaneously using three-dimensional (3D) deformable image registration (single inputs or multi-atlas). Twenty-three of the major lower limb skeletal muscles were segmented from five subjects, with an average Dice similarity coefficient of 0.72, and average absolute relative volume error (RVE) of 12.7% (average relative volume error of -2.2%) considering the optimal subject combinations. The multi-atlas approach showed slightly better accuracy (average DSC: 0.73; average RVE: 1.67%). Segmented MR imaging datasets of the lower limb are not widely available in the literature, limiting the potential of new, probabilistic methods such as deep learning to be used in the context of muscle segmentation. In this work, Non-linear deformable image registration is used to generate 69 manually checked, segmented, 3D, artificial datasets, allowing access for future studies to use these new methods, with a large amount of reliable reference data.

Single‐leg disuse decreases skeletal muscle strength, size, and power in uninjured adults: A systematic review and meta‐analysis

We aimed to quantify declines from baseline in lower limb skeletal muscle size and strength of uninjured adults following single-leg disuse. We searched EMBASE, Medline, CINAHL, and CCRCT up to 30 January 2022. Studies were included in the systematic review if they (1) recruited uninjured participants; (2) were an original experimental study; (3) employed a single-leg disuse model; and (4) reported muscle strength,size, or power data following a period of single-leg disuse for at least one group without a countermeasure. Studies were excluded if they (1) did not meet all inclusion criteria; (2) were not in English; (3) reported previously published muscle strength, size, or power data; or (4) could not be sourced from two different libraries, repeated online searches, and the authors. We used the Cochrane Risk of Bias Assessment Tool to assess risk of bias. We then performed random-effects meta-analyses on studies reporting measures of leg extension strength and extensor size. Our search revealed 6548 studies, and 86 were included in our systematic review. Data from 35 and 20 studies were then included in the meta-analyses for measures of leg extensor strength and size, respectively (40 different studies). No meta-analysis for muscle power was performed due to insufficient homogenous data. Effect sizes (Hedges' gav ) with 95% confidence intervals for leg extensor strength were all durations=-0.80 [-0.92, -0.68] (n=429 participants; n=68 aged 40years or older; n≥78 females); ≤7days of disuse=-0.57 [-0.75, -0.40] (n=151); >7days and ≤14days=-0.93 [-1.12, -0.74] (n=206); and >14days=-0.95 [-1.20, -0.70] (n=72). Effect sizes for measures of leg extensor size were all durations=-0.41 [-0.51, -0.31] (n=233; n=32 aged 40years or older; n≥42 females); ≤7days=-0.26 [-0.36, -0.16] (n=84); >7days and ≤14days=-0.49 [-0.67, -0.30] (n=102); and >14days=-0.52 [-0.74, -0.30] (n=47). Decreases in leg extensor strength (cast: -0.94 [-1.30, -0.59] (n=73); brace: -0.90 [-1.18, -0.63] (n=106)) and size (cast: -0.61[-0.87, -0.35] (n=41); brace: (-0.48 [-1.04, 0.07] (n=41)) following 14days of disuse did not differ for cast and brace disuse models. Single-leg disuse in adults resulted in a decline in leg extensor strength and size that reached a nadir beyond 14days. Bracing and casting led to similar declines in leg extensor strength and size following 14days of disuse. Studies including females and males and adults over 40years of age are lacking.

Association of Different Obesity Phenotypes with Sarcopenia in Han Chinese Middle-Aged and Elderly with Type 2 Diabetes Individuals.

To investigate the relationship between different obesity phenotypes and sarcopenia in hospitalized Chinese patients with type 2 diabetes mellitus (T2DM). This cross-sectional study included 385 men. Anthropometric measurements including applied the determination method of Dual-energy X-ray absorptiometry (DXA) determination of limb skeletal muscle mass index (ASMI) and blood samples were analyzed. The people were divided into four groups according to body mass index (BMI) (≥24kg/m2) and waist circumference (WC) (female ≥85cm, male ≥90cm). Group A (BMI and WC were normal), Group B (BMI was normal and high WC), Group C (high BMI and WC were normal), and Group D (BMI and WC were abnormal). The prevalence rates of sarcopenia and abdominal obesity were 32.2% and 74.0%, respectively. The detection rate of lower ASMI decreased gradually from Group A to Group D(74.6% vs 68.3% vs 54.5% vs 51.6%, χ 2 =14.243, P=0.003). Logistic analysis showed that the risk of lower ASMI were decreased by 62.4% (95% CI: 0.149-0.950, P = 0.039) in Group C and 68.8% (95% CI: 0.165-0.593, P = 0.000) in Group D compared with Group A, respectively. The risk of lower ASMI were increased 4.153-fold (95% CI: 2.623-6.576, P = 0.000) in male. Male (OR = 4.065, 95% CI: 2.246-7.356, P = 0.000) and WC (OR = 1.053, 95% CI: 1.004-1.104, P = 0.033) were risk factors for lower ASMI, but the risk of lower ASMI was decreased by 32% (95% CI: 0.5744-0.804, P = 0.000) by elevated BMI in the overweight and obese group (Group C and Group D). The prevalence of sarcopenia and abdominal obesity was elevated in han Chinese middle-aged and elderly patients with T2DM. Being overweight or obesity as defined by BMI protect against sarcopenia, while abdominal obesity increases the risk of sarcopenia.

Bovine HOXA11 Gene Identified from RNA-Seq: mRNA Profile Analysis and Genetic Variation Detection Using ME Method and Their Associations with Carcass Traits.

The Homeobox A11 (HOXA11) gene regulates limb skeletal development and muscle growth, thus, it was selected as a candidate gene for bovine carcass traits. In this study, we analyzed the mRNA expression level of HOXA11 in various tissues and cells, and determined the genetic variations in the HOXA11 gene, which might be used as molecular markers for cattle breeding. The mRNA expression profiles of HOXA11 in bovine different tissues showed that HOXA11 was highly expressed in both fat and muscle. The gene expression trend of HOXA11 in myoblasts and adipocytes indicated that HOXA11 might be involved in the differentiation of bovine myoblasts and adipocytes. The data in the Ensembl database showed that there are two putative insertion/deletion (InDel) polymorphisms in the bovine HOXA11 gene. The insertion site (rs515880802) was located in the upstream region (NC_037331.1: g. 68853364-68853365) and named as P1-Ins-4-bp, and the deletion site (rs517582703) was located in the intronic region (NC_037331.1: g. 68859510-68859517) and named as P2-Del-8-bp. These polymorphisms within the HOXA11 gene were identified and genotyped by PCR amplification, agarose gel electrophoresis and DNA sequencing in the 640 Shandong Black Cattle Genetic Resource (SDBCGR) population. Moreover, the mutation frequency was very low after detection, so the mathematical expectation (ME) method was used for detection. Statistical analysis demonstrated that P1-Ins-4-bp was significantly correlated with the beef shoulder (p = 0.012) and tongue root (p = 0.004). Meanwhile, P2-Del-8-bp displayed a significant correlation with the back tendon (p = 0.008), money tendon (p = 2.84 × 10-4), thick flank (p = 0.034), beef shin (p = 9.09 × 10-7), triangle thick flank (p = 0.04), triangle flank (p = 1.00 × 10-6), rump (p = 0.018) and small tenderloin (p = 0.043) in the female SDBCGR population. In summary, these outcomes may provide a new perspective for accelerating the molecular breeding of cattle through marker-assisted selection (MAS) strategies.

Effects of beta-hydroxy beta-methyl butyrate calcium combined with exercise therapy in patients with cardiac disease: a study protocol for clinical trial

IntroductionThe current treatment for heart disease consists of exercise therapy in addition to pharmacotherapy, nutritional support and lifestyle guidance. In general, nutritional support focuses on protein, salt and energy restrictions,...

Relationships between Lower Limb Skeletal Muscle Morphology and Physical Function and Life Spaces of Female Users of Day-care Rehabilitation with Sarcopenia

Relationships between Lower Limb Skeletal Muscle Morphology and Physical Function and Life Spaces of Female Users of Day-care Rehabilitation with Sarcopenia

Noninvasive monitoring of muscle atrophy and bone metabolic disorders using dual-energy X-ray absorptiometry in diabetic mice.

Tracking metabolic changes in skeletal muscle and bone using animal models of diabetes mellitus (DM) provides important insights for the management of DM complications. In this study, we aimed to establish a method for monitoring changes in body composition characteristics, such as fat mass, skeletal muscle mass (lean mass), bone mineral density, and bone mineral content, during DM progression using a dual-energy X-ray absorptiometry (DXA) system in a mouse model of streptozotocin (STZ)-induced type 1 DM. In the DM model, STZ administration resulted in increased blood glucose levels, increased water and food intake, and decreased body weight. Serum insulin levels were significantly decreased on day 30 of STZ administration. The DXA analysis revealed significant and persistent decreases in fat mass, lower limb skeletal muscle mass, and bone mineral content in DM mice. We measured tibialis anterior (TA) muscle weight and performed a quantitative analysis of tibial microstructure by micro-computed tomography imaging in DM mice. The TA muscle weight of DM mice was significantly lower than that of control mice. In addition, the trabecular bone volume fraction, trabecular thickness, trabecular number, and cortical thickness were significantly decreased in DM mice. Pearson's product-moment correlation coefficient analysis showed a high correlation between the DXA-measured and actual body composition. In conclusion, longitudinal measurement of body composition changes using a DXA system may be useful for monitoring abnormalities in muscle and bone metabolism in animal models of metabolic diseases such as DM mice.

The G protein-coupled receptor ligand apelin-13 ameliorates skeletal muscle atrophy induced by chronic kidney disease.

Targeting of the apelin-apelin receptor (Apj) system may serve as a useful therapeutic intervention for the management of chronic kidney disease (CKD)-induced skeletal muscle atrophy. We investigated the roles and efficacy of the apelin-Apj system in CKD-induced skeletal muscle atrophy. The 5/6-nephrectomized mice were used as CKD models. AST-120, a charcoal adsorbent of uraemic toxins (8 w/w% in diet), or apelin (1μmol/kg) was administered to CKD mice to investigate the mechanism and therapeutic potential of apelin on CKD-induced skeletal muscle atrophy. The effect of indoxyl sulfate, a uraemic toxin, or apelin on skeletal muscle atrophy was evaluated using mouse myoblast cells (C2C12 cells) in vitro. Skeletal muscle atrophy developed over time following nephrectomy at 12weeks, as confirmed by a significant increase of atrogin-1 and myostatin mRNA expression in the gastrocnemius (GA) muscle and a decrease of lower limb skeletal muscle weight (P<0.05, 0.01 and 0.05, respectively). Apelin expression in GA muscle was significantly decreased (P<0.05) and elabela, another Apj endogenous ligand, tended to show a non-significant decrease at 12weeks after nephrectomy. Administration of AST-120 inhibited the decline of muscle weight and increase of atrogin-1 and myostatin expression. Apelin and elabela expression was slightly improved by AST-120 administration but Apj expression was not, suggesting the involvement of uraemic toxins in endogenous Apj ligand expression. The administration of apelin at 1.0μmol/kg for 4weeks to CKD mice suppressed the increase of atrogin-1 and myostatin, increased apelin and Apj mRNA expression at 30min after apelin administration and significantly ameliorated weight loss and a decrease of the cross-sectional area of hindlimb skeletal muscle. This study demonstrated for the first time the association of the Apj endogenous ligand-uraemic toxin axis with skeletal muscle atrophy in CKD and the utility of therapeutic targeting of the apelin-Apj system.

P62/Sqstm1 rescue in muscle retards the progression of steatohepatitis in p62/Sqstm1-null mice fed a high-fat diet.

Introduction: Obesity is a risk factor for many diseases because it leads to a reduction in skeletal muscle mass and promotes insulin resistance. p62/Sqstm1-knockout mice are a model of metabolic syndrome; show obesity, insulin resistance, and non-alcoholic fatty liver (NAFL); and develop non-alcoholic steatohepatitis (NASH) in response to the feeding of a high-fat diet (HFD). These phenotypes suggest that muscle p62 may prevent obesity-induced muscle dysfunction. In the present study, we aimed to determine the effects of muscle p62 on skeletal muscle mass, muscle strength, insulin resistance, and NASH pathology. Methods: We generated muscle-specific p62 gene rescue mice (p62-mRes), which express p62 only in muscle and were derived from p62-knock out mice (p62 KIKI ) using the cre/loxp system. p62 KIKI and p62-mRes mice were fed an HFD for 20 weeks and their phenotypes were compared. Results: HFD-feeding caused severe obesity in both p62 KIKI and p62-mRes mice, but there was no effect of muscle p62 on body mass. Limb skeletal muscle mass, grip strength, and the cross-sectional area of muscle fibers were higher in p62-mRes mice than in p62 KIKI . The glucose tolerance and insulin sensitivity of the p62-mRes mice were also superior. The protein expression of mechanistic target of rapamycin, which promotes muscle protein synthesis, and GLUT4, a glucose transporter in skeletal muscle, were higher in the p62-mRes mice. p62 KIKI mice developed severe NASH when fed an HFD, but the progression of NASH was retarded by p62 gene rescue in muscle, and the expression of Tgf-β1, which encodes a factor that promotes hepatic fibrosis, was reduced. Conclusion: Rescue of muscle-specific p62 in the whole-body p62 knock-out mice ameliorates the insulin resistance and retards the progression of NASH caused by systemic p62 ablation.

Bone mineral density, limb muscle mass, muscle strength, and exercise capacity are reduced in female patients with distal radius fractures when the unaffected side grip strength is less than 18 kg

BackgroundPrevention of domino effects after distal radius fractures is important for improving life expectancy. Fragility fractures secondary to falls are associated with decreased bone mineral density, muscle strength, and exercise capacity. Grip strength is one of the simplest and most useful tests to comprehensively judge muscle strength. The purpose of this study was to examine whether grip strength is associated with bone mineral density, limb muscle mass, muscle strength, and exercise capacity, by comparing patient backgrounds based on the presence or absence of grip weakness in female patients with distal radius fractures. MethodsThis study included women with distal radius fractures who visited our orthopedics outpatient department between April 2015 and April 2020. Bone mineral density, limb muscle mass, skeletal muscle mass index, muscle strength (grip strength on unaffected side and quadriceps muscle strength), the Timed Up and Go test, and the Two-Step test were evaluated six to eight weeks after injury. Patients were divided into two groups according to the cutoff value of grip strength (18–21 kg), and 90 age-adjusted and matched participants were compared and examined. ResultsAt the cutoff value of 18 kg, a significant decrease in lumbar spine and total proximal femur bone mineral density (p < 0.05, p < 0.05), limb muscle mass and skeletal muscle mass index (p < 0.01, p < 0.05), quadriceps femoris muscle strength (p < 0.01), the Timed Up and Go test (p < 0.05), and the Two-Step test (p < 0.01), was observed in the grip-weakness group compared to that in the no-grip-weakness group. ConclusionsIn women with distal radius fracture and grip strength <18 kg on the unaffected side, bone mineral density, limb muscle mass, quadriceps femoris strength, and exercise capacity may be reduced. These results suggest reduced grip strength may be an indicator for further testing to prevent domino effects.

Effects of vibration training on activation characteristics of lower limb skeletal muscle and physiological load in middle aged and elderly people aged 50-65

目的: 观察中老年人进行振动训练时下肢骨骼肌激活特征和生理负荷指标,探讨将振动训练应用于中老年人的可行性。方法: 选取28名50～65岁健康中老年人作为研究对象,分别在振动条件下(VT)和无振动条件下(NT)进行5次40 s静力半蹲练习,测试下肢主要肌群表面肌电和生理负荷指标。结果: ①VT受试者腓肠肌内侧(MG)、腓肠肌外侧(LG)、胫骨前肌(TA)、股直肌(RF)、股内侧肌(VM)、股外侧肌(VL)、股二头肌(BF)、半腱肌(ST)均方根振幅(RMS)显著高于NT(P＜0.01,P＜0.05),VL、BF、ST、MG、LG、TA平均功率频率(MPF)显著高于NT(P＜0.05);VM、VL、BF、MG、LG、TA平均功率斜率(MPF slope)显著高于NT(P＜0.05);②VT受试者心率和摄氧量显著高于NT(P＜0.05),主观疲劳等级(RPE)与NT比较无显著差异;③VT受试者尿素氮与NT无显著差异。结论: 50～65岁中老年人采用施加振动刺激的静力半蹲练习可以使机体募集更多的运动单位和更高比例的快肌纤维参与工作,在不增加主观疲劳感的基础上增加运动强度,同时未发现肌肉损伤。.

Visual three-dimensional spatial distribution of motor neurons innervating superficial limb muscles in mice.

The coordination of motor function in the spinal cord depends on selective connections between distinct classes of motor neurons and their target muscles. However, knowledge regarding the anatomical connections between the superficial limb skeletal muscles and the motor neurons that innervate them is limited. In this study, with a combination of the multiple retrograde tracing method with 3DISCO clearing, we explored the spatial distribution of different motor neuron pools targeting specific superficial muscles of the forelimbs or hindlimbs in mouse spinal cords, which were dominated by the radial, median, ulnar, or sciatic nerve. This study reveals the precise interrelationship among different motor neuron pools innervating limb muscles under the same space and time. The data will help to further understand the neural loop and muscular motor coordination.

Estrogen-related receptor alpha is an AMPK-regulated factor that promotes ischemic muscle revascularization and recovery in diet-induced obese mice.

Obesity and type II diabetes are leading causes of peripheral arterial disease (PAD), which is characterized by vascular insufficiency and ischemic damage in the limb skeletal muscle. Glycemic control is not sufficient to prevent progression of PAD, and molecular targets that can promote muscle neo‐angiogenesis in obesity and diabetes remain poorly defined. Here, we have investigated whether nuclear receptor estrogen‐related receptor alpha (ERRα) can promote ischemic revascularization in the skeletal muscles of diet‐induced obese (DIO) mice. Using muscle‐specific ERRα transgenic mice, we found that ERRα overexpression promotes revascularization, marked by increased capillary staining and muscle perfusion in DIO mice after hindlimb ischemic injury. Furthermore, ERRα facilitates repair and restoration of skeletal muscle myofiber size after limb ischemia in DIO mice. The ameliorative effects of ERRα overexpression did not involve the prevention of weight gain, hyperglycemia or glucose/insulin intolerance, suggesting a direct role for ERRα in promoting angiogenesis. Interestingly, levels of endogenous ERRα protein are suppressed in the skeletal muscles of DIO mice compared to lean controls, coinciding with the suppression of angiogenic gene expression, and reduced AMPK signaling in the DIO skeletal muscles. Upon further investigating the link between AMPK and ERRα, we found that AMPK activation increases the expression and recruitment of ERRα protein to specific angiogenic gene promoters in muscle cells. Further, the induction of angiogenic factors by AMPK activators in muscle cells is blocked by repressing ERRα. In summary, our results identify an AMPK/ERRα‐dependent angiogenic gene program in the skeletal muscle, which is repressed by DIO, and demonstrate that forced ERRα activation can promote ischemic revascularization and muscle recovery in obesity.

New Perspectives for Postmortem Human Satellite Cells of Different Embryological Origin

Human postmortem skeletal muscles are a unique source of satellite cells for skeletal muscle regenerative studies. Presomite and somite satellite cells obtained by postmortem muscles have been established as populations of human skeletal muscle precursor cells able to proliferate and differentiate in vitro. It is extremely interesting to have access to a large amount of postmortem human skeletal muscle precursor cells, especially from craniofacial as well as limb skeletal muscles in order to evaluate their potential application not only for the fundamental understanding of muscle physiology and diseases but also for drug testing in a challenging 3D-shaping muscles like skeletal muscle microphysiological systems.

CYB5R3 overexpression preserves skeletal muscle mitochondria and autophagic signaling in aged transgenic mice

Cytochrome b5 reductase 3 (CYB5R3) overexpression activates respiratory metabolism and exerts prolongevity effects in transgenic mice, mimicking some of the salutary effects of calorie restriction. The aim of our study was to understand how CYB5R3 overexpression targets key pathways that modulate the rate of aging in skeletal muscle, a postmitotic tissue with a greater contribution to resting energy expenditure. Mitochondrial function, autophagy and mitophagy markers were evaluated in mouse hind limb skeletal muscles from young-adult (7 months old) and old (24 months old) males of wild-type and CYB5R3-overexpressing genotypes. Ultrastructure of subsarcolemmal and intermyofibrillar mitochondria was studied by electron microscopy in red gastrocnemius. CYB5R3, which was efficiently overexpressed and targeted to skeletal muscle mitochondria regardless of age, increased the abundance of complexes I, II, and IV in old mice and prevented the age-related decrease of complexes I, III, IV, and V and the mitofusin MFN-2. ATP was significantly decreased by aging, which was prevented by CYB5R3 overexpression. Coenzyme Q and the mitochondrial biogenesis markers TFAM and NRF-1 were also significantly diminished by aging, but CYB5R3 overexpression did not protect against these declines. Both aging and CYB5R3 overexpression upregulated SIRT3 and the mitochondrial fission markers FIS1 and DRP-1, although with different outcomes on mitochondrial ultrastructure: old wild-type mice exhibited mitochondrial fragmentation whereas CYB5R3 overexpression increased mitochondrial size in old transgenic mice concomitant with an improvement of autophagic recycling. Interventions aimed at stimulating CYB5R3 could represent a valuable strategy to counteract the deleterious effects of aging in skeletal muscle.Graphical abstract

Impact of the Birth Transition on Striated Muscle Function in Normal Development

Considerable changes are expected in the regulation of myocardial and limb skeletal muscle perfusion from the pre‐ to post‐natal condition based on changes in gravitational force, work load, and arterial O2 content. Yet the impact of birth on the growth and function of microvasculature in striated muscle is poorly understood. Our objective was to assess resting and maximal microvascular flow in the cardiac left ventricle (LV; with high workload before and after birth), and biceps femoris (BF; hindlimb muscle with little workload before birth). We hypothesized that resting flow in the fetus exceeds that in the neonate because of low fetal arterial O2 content, but that flow reserve is greater in the neonate in order to support ambulation. We expected this increase in reserve to be greater in skeletal than myocardial muscle.Fetuses (N=8) were instrumented at 130 d gestational age (dGA, birth is at 146 d) and studied exteriorized from the uterus at 135 dGA. Lambs (N=8) were instrumented 2 d after birth and studied at 5 d. Instrumentation included arterial, venous, and left atrial catheters for systemic pressure monitoring, arterial blood sampling, and drug delivery; and an inflatable occluder around the descending thoracic aorta. Myocardial perfusion (Q) in mL/min/g of tissue was assessed by transthoracic contrast echocardiography at rest, during adenosine‐induced hyperemia, and during combined hyperemia and increased perfusion pressure produced by transient constriction of the postductal aorta. Work was determined by the product of heart rate and perfusion pressure. Hindlimb BF muscle Q was assessed at rest, and during contractile work produced by electrostimulation (2 Hz, 10 mA). Differences were assessed by the Mann‐Whitney U‐test. One fetus and one lamb were excluded from analysis because of abnormal blood gasses at the time of study.At rest, LV myocardial Q was 2‐fold higher in fetuses than neonates (Fig 1A), as was Q normalized to work; whereas, O2 delivery was similar between groups (Fig 1B). Maximal flow during hyperemia followed a similar pattern, with fetal Q, as well as Q per work, exceeding that in the neonate by a factor of 7, whereas maximal O2 delivery per work was similar between age groups. Skeletal muscle (BF) flow in the fetus was highly variable both at rest and during exercise. Median resting Q, resting O2 delivery, and exercised flow were all at least 5‐fold higher in the fetus than neonate, however the difference only reached statistical significance for resting flow (Fig 1A,B). Exercise O2 delivery was similar between ages. Flow reserve was similar between the fetus and neonate in both myocardium and skeletal muscle (Fig 1C).At rest, elevated flow in the fetal LV supported similar levels of O2 delivery per work as found in the newborn. Surprisingly, there was a tendency for increased O2 delivery in the fetal skeletal muscle compared to the newborn; we speculate that this reflects differences in regulation of non‐nutritive flow between the ages studied. Overall, the results of this study suggest that despite the dramatically different physiological circumstances between the fetus and newborn, microvascular growth is regulated to preserve similar levels of flow reserve in both.