D-galactose might mediate some of the skeletal muscle hypertrophy-promoting effects of milk-A nutrient to consider for sarcopenia?

Sarcopenia is a process of progressive aging-associated loss of skeletal muscle mass (SMM) recognized as a serious global health issue contributing to frailty and increased all-cause mortality. Exercise and nutritional interventions (particularly intake of dairy products and milk) demonstrate good efficacy, safety, and broad applicability. Here, we propose that at least some of the well-documented favorable effects of milk and milk-derived protein supplements on SMM might be mediated by D-galactose, a monosaccharide present in large quantities in milk in the form of disaccharide lactose (milk sugar). We suggest that ingestion of dairy products results in exposure to D-galactose in concentrations metabolized primarily via the Leloir pathway with the potential to (i) promote anabolic signaling via maintenance of growth factor (e.g., insulin-like growth factor 1 [IGF-1]) receptor mature glycosylation patterns; and (ii) provide extracellular (liver glycogen) and intracellular substrates for short (muscle glycolysis) and long-term (muscle glycogen, intramyocellular lipids) energy availability. Additionally, D-galactose might optimize the metabolic function of skeletal muscles by increasing mitochondrial content and stimulating glucose and fatty acid utilization. The proposed potential of D-galactose to promote the accretion of SMM is discussed in the context of its therapeutic potential in sarcopenia.

Nuclear-localized androgen receptor content following resistance exercise training is associated with hypertrophy in males but not females.

Androgen receptor (AR) content has been implicated in the differential response between high and low responders following resistance exercise training (RET). However, the influence of AR expression on acute skeletal muscle damage and whether it may influence the adaptive response to RET in females is poorly understood. Thus, the purpose of this exploratory examination was to 1) investigate changes in AR content during skeletal muscle repair and 2) characterize AR-mediated sex-based differences following RET. A skeletal muscle biopsy from the vastus lateralis was obtained from 26 healthy young men (n = 13) and women (n = 13) at baseline and following 300 eccentric kicks. Subsequently, participants performed 10 weeks of full-body RET and a final muscle biopsy was collected. In the untrained state, AR mRNA expression was associated with paired box protein-7 (PAX7) mRNA in males. For the first time in human skeletal muscle, we quantified AR content in the myofiber and localized to the nucleus where AR has been shown to trigger cellular outcomes related to growth. Upon eccentric damage, nuclear-associated AR (nAR) content increased (p < .05) in males and not females. Males with the greatest increase in cross-sectional area (CSA) post-RET had more (p < .05) nAR content than females with the greatest gain CSA. Collectively, skeletal muscle damage and RET increased AR protein, and both gene and hypertrophy measures revealed sex differences in relation to AR. These findings suggest that AR content but more importantly, nuclear localization, is a factor that differentiates RET-induced hypertrophy between males and females.

Primary cilia in satellite cells are the mechanical sensors for muscle hypertrophy.

Skeletal muscle atrophy is commonly associated with aging, immobilization, muscle unloading, and congenital myopathies. Generation of mature muscle cells from skeletal muscle satellite cells (SCs) is pivotal in repairing muscle tissue. Exercise therapy promotes muscle hypertrophy and strength. Primary cilium is implicated as the mechanical sensor in some mammalian cells, but its role in skeletal muscle cells remains vague. To determine mechanical sensors for exercise-induced muscle hypertrophy, we established three SC-specific cilium dysfunctional mouse models-Myogenic factor 5 (Myf5)-Arf-like Protein 3 (Arl3)-/-, Paired box protein Pax-7 (Pax7)-Intraflagellar transport protein 88 homolog (Ift88)-/-, and Pax7-Arl3-/--by specifically deleting a ciliary protein ARL3 in MYF5-expressing SCs, or IFT88 in PAX7-expressing SCs, or ARL3 in PAX7-expressing SCs, respectively. We show that the Myf5-Arl3-/- mice develop grossly the same as WT mice. Intriguingly, mechanical stimulation-induced muscle hypertrophy or myoblast differentiation is abrogated in Myf5-Arl3-/- and Pax7-Arl3-/- mice or primary isolated Myf5-Arl3-/- and Pax7-Ift88-/- myoblasts, likely due to defective cilia-mediated Hedgehog (Hh) signaling. Collectively, we demonstrate SC cilia serve as mechanical sensors and promote exercise-induced muscle hypertrophy via Hh signaling pathway.

Genome-wide association study of exercise-induced skeletal muscle hypertrophy and the construction of predictive model.

The aim of the current study was to investigate interindividual differences in muscle thickness of the rectus femoris (MTRF) following 12 wk of resistance training (RT) or high-intensity interval training (HIIT) to explore the genetic architecture underlying skeletal muscle hypertrophy and to construct predictive models. We conducted musculoskeletal ultrasound assessments of the MTRF response in 440 physically inactive adults after the 12-wk exercise period. A genome-wide association study was used to identify variants associated with the MTRF response, separately for RT and HIIT. Using the polygenic predictor score (PPS), we estimated the genetic contribution to exercise-induced hypertrophy. Predictive models for the MTRF response were constructed using random forest (RF), support vector mac (SVM), and generalized linear model (GLM) in 10 cross-validated approaches. MTRF increased significantly after both RT (8.8%, P < 0.05) and HIIT (5.3%, P < 0.05), but with considerable interindividual differences (RT: -13.5 to 38.4%, HIIT: -14.2 to 30.7%). Eleven lead single-nucleotide polymorphisms in RT and eight lead single-nucleotide polymorphisms in HIIT were identified at a significance level of P < 1 × 10-5. The PPS was associated with the MTRF response, explaining 47.2% of the variation in response to RT and 38.3% of the variation in response to HIIT. Notably, the GLM and SVM predictive models exhibited superior performance compared with RF models (P < 0.05), and the GLM demonstrated optimal performance with an area under curve of 0.809 (95% confidence interval: 0.669-0.949). Factors such as PPS, baseline MTRF, and exercise protocol exerted influence on the MTRF response to exercise, with PPS being the primary contributor. The GLM and SVM predictive model, incorporating both genetic and phenotypic factors, emerged as promising tools for predicting exercise-induced skeletal muscle hypertrophy.NEW & NOTEWORTHY The interindividual variability induced muscle hypertrophy by resistance training (RT) or high-intensity interval training (HIIT) and the associated genetic architecture remain uncertain. We identified genetic variants that underlie RT- or HIIT-induced muscle hypertrophy and established them as pivotal factors influencing the response regardless of the training type. The genetic-phenotype predictive model developed has the potential to identify nonresponders or individuals with low responsiveness before engaging in exercise training.

Adverse Skeletal Muscle Adaptations in Individuals Born Preterm-A Comprehensive Review.

Infants born preterm face an increased risk of deleterious effects on lung and brain health that can significantly alter long-term function and quality of life and even lead to death. Moreover, preterm birth is also associated with a heightened risk of diabetes and obesity later in life, leading to an increased risk of all-cause mortality in young adults born prematurely. While these preterm-birth-related conditions have been well characterized, less is known about the long-term effects of preterm birth on skeletal muscle health and, specifically, an individual's skeletal muscle hypertrophic potential later in life. In this review, we discuss how a confluence of potentially interrelated and self-perpetuating elements associated with preterm birth might converge on anabolic and catabolic pathways to ultimately blunt skeletal muscle hypertrophy, identifying critical areas for future research.

Role of mechanoregulation in mast cell-mediated immune inflammation of the smooth muscle in the pathophysiology of esophageal motility disorders.

Major esophageal disorders involve obstructive transport of bolus to the stomach, causing symptoms of dysphagia and impaired clearing of the refluxed gastric contents. These may occur due to mechanical constriction of the esophageal lumen or loss of relaxation associated with deglutitive inhibition, as in achalasia-like disorders. Recently, immune inflammation has been identified as an important cause of esophageal strictures and the loss of inhibitory neurotransmission. These disorders are also associated with smooth muscle hypertrophy and hypercontractility, whose cause is unknown. This review investigated immune inflammation in the causation of smooth muscle changes in obstructive esophageal bolus transport. Findings suggest that smooth muscle hypertrophy occurs above the obstruction and is due to mechanical stress on the smooth muscles. The mechanostressed smooth muscles release cytokines and other molecules that may recruit and microlocalize mast cells to smooth muscle bundles, so that their products may have a close bidirectional effect on each other. Acting in a paracrine fashion, the inflammatory cytokines induce genetic and epigenetic changes in the smooth muscles, leading to smooth muscle hypercontractility, hypertrophy, and impaired relaxation. These changes may worsen difficulty in the esophageal transport. Immune processes differ in the first phase of obstructive bolus transport, and the second phase of muscle hypertrophy and hypercontractility. Moreover, changes in the type of mechanical stress may change immune response and effect on smooth muscles. Understanding immune signaling in causes of obstructive bolus transport, type of mechanical stress, and associated smooth muscle changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.NEW & NOTEWORTHY Esophageal disorders such as esophageal stricture or achalasia, and diffuse esophageal spasm are associated with smooth muscle hypertrophy and hypercontractility, above the obstruction, yet the cause of such changes is unknown. This review suggests that smooth muscle obstructive disorders may cause mechanical stress on smooth muscle, which then secretes chemicals that recruit, microlocalize, and activate mast cells to initiate immune inflammation, producing functional and structural changes in smooth muscles. Understanding the immune signaling in these changes may help pathophysiology-based prevention and targeted treatment of esophageal motility disorders.

Assessing Muscle Protein Synthesis Rates In Vivo in Humans: The Deuterated Water (2H2O) Method.

Skeletal muscle tissue is in a constant state of turnover, with muscle tissue protein synthesis and breakdown rates ranging between 1% and 2% across the day in vivo in humans. Muscle tissue remodeling is largely controlled by the up- and down-regulation of muscle tissue protein synthesis rates. Research studies generally apply stable isotope-labeled amino acids to assess muscle protein synthesis rates in vivo in humans. Following labeled amino acid administration in a laboratory setting, muscle tissue samples are collected over several hours to assess the incorporation rate of these labeled amino acids in muscle tissue protein. To allow quantification of bulk muscle protein synthesis rates over more prolonged periods, the use of deuterated water methodology has regained much interest. Ingestion of daily boluses of deuterium oxide results in 2H enrichment of the body water pool. The available 2H-atoms become incorporated into endogenously synthesized alanine primarily through transamination of pyruvate in the liver. With 2H-alanine widely available to all tissues, it becomes incorporated into de novo synthesized tissue proteins. Assessing the increase in tissue protein-bound 2H-alanine enrichment in muscle biopsy samples over time allows for the calculation of muscle protein synthesis rates over several days or even weeks. As the deuterated water method allows for the assessment of muscle tissue protein synthesis rates under free-living conditions in nonlaboratory settings, there is an increasing interest in its application. This manuscript describes the theoretical background of the deuterated water method and offers a comprehensive tutorial to correctly apply the method to determine bulk muscle protein synthesis rates in vivo in humans.

Conserved and species-specific transcriptional responses to daily programmed resistance exercise in rat and mouse.

Mice are often used in gain or loss of function studies to understand how genes regulate metabolism and adaptation to exercise in skeletal muscle. Once-daily resistance training with electrical nerve stimulation produces hypertrophy of the dorsiflexors in rat, but not in mouse. Using implantable pulse generators, we assessed the acute transcriptional response (1-h post-exercise) after 2, 10, and 20 days of training in free-living mice and rats using identical nerve stimulation paradigms. RNA sequencing revealed strong concordance in the timecourse of many transcriptional responses in the tibialis anterior muscles of both species including responses related to "stress responses/immediate-early genes, and "collagen homeostasis," "ribosomal subunits," "autophagy," and "focal adhesion." However, pathways associated with energy metabolism including "carbon metabolism," "oxidative phosphorylation," "mitochondrial translation," "propanoate metabolism," and "valine, leucine, and isoleucine degradation" were oppositely regulated between species. These pathways were suppressed in the rat but upregulated in the mouse. Our transcriptional analysis suggests that although many pathways associated with growth show remarkable similarities between species, the absence of an actual growth response in the mouse may be because the mouse prioritizes energy metabolism, specifically the replenishment of fuel stores and intermediate metabolites.

Stuart has got the PoWeR! Skeletal muscle adaptations to a novel heavy progressive weighted wheel running exercise model in C57BL/6 mice.

Murine exercise models are developed to study the molecular and cellular mechanisms regulating muscle mass. A progressive weighted wheel running model, named 'PoWeR', was previously developed to serve as a more translatable alternative to involuntary resistance-type exercise models in rodents, such as synergist ablation. However, mice still run great distances despite the added resistance as evidenced by a large glycolytic-to-oxidative shift in muscle fibre type. Thus, PoWeR reflects a blended resistance/endurance model. In an attempt to bias PoWeR further towards resistance-type exercise, we developed a novel heavy PoWeR model (hPoWeR) utilizing higher wheel loads (max of 12.5 g vs 6 g). Adult male C57BL/6 mice voluntarily performed an 8-week progressive loading protocol (PoWeR or hPoWeR). Running distance peaked at ∼5-6 km day-1 in both treatments and was maintained by PoWeR mice, but declined in the hPoWeR mice as load increased beyond 7.5 g. Peak isometric force of the gastrocnemius-soleus-plantaris complex tended to increase in wheel running treatments. Soleus mass increased by 19% and 24% in PoWeR and hPoWeR treatments, respectively, and plantaris fibre cross-sectional area was greater in hPoWeR, compared to PoWeR. There were fewer glycolytic and more oxidative fibres in the soleus and plantaris muscles in the PoWeR treatment, but not hPoWeR. Collectively, these data suggest hPoWeR may modestly alter skeletal muscle supporting the aim of better reflecting typical resistance training adaptations, in line with decreased running volume and exposure to higher resistance. Regardless, PoWeR remains an effective hypertrophic concurrent training model in mice.

Beta2-Adrenergic Stimulation Induces Resistance Training-Like Adaptations in Human Skeletal Muscle: Potential Role of KLHL41.

Skeletal muscle mass plays a pivotal role in metabolic function, but conditions such as bed rest or injury often render resistance training impractical. The beta2-adrenergic receptor has been highlighted as a potential target to promote muscle hypertrophy and treat atrophic conditions. Here, we investigate the proteomic changes associated with beta2-adrenergic-mediated muscle hypertrophy, using resistance training as a hypertrophic comparator. We utilize MS-based proteomics to map skeletal muscle proteome remodeling in response to beta2-adrenergic stimulation or resistance training as well as cell model validation. We report that beta2-adrenergic stimulation mimics multiple features of resistance training in proteome-wide remodeling, comprising systematic upregulation of ribosomal subunits and concomitant downregulation of mitochondrial proteins. Approximately 20% of proteins were regulated in both conditions, comprising proteins involved in steroid metabolism (AKR1C1, AKR1C2, AKRC1C3), protein-folding (SERPINB1), and extracellular matrix organization (COL1A1, COL1A2). Among overall most significantly upregulated proteins were kelch-like family members (KLHL) 40 and 41. In follow-up experiments, we identify KLHL41 as having novel implications for beta2-adrenergic-mediated muscle hypertrophy. Treating C2C12 cells with beta2-agonist for 96 h increased myotube diameter by 48% (p < 0.001). This anabolic effect was abolished by prior knockdown of KLHL41. Using siRNA, KLHL41 abundance was decreased by 60%, and the anabolic response to beta2-agonist was diminished (+ 15%, i.e., greater in the presence of KLHL41, knock-down × treatment: p = 0.004). In conclusion, protein-wide remodeling induced by beta2-adrenergic stimulation mimics multiple features of resistance training, and thus the beta2-adrenergic receptor may be a target with therapeutic potential in the treatment of muscle wasting conditions without imposing mechanical load.

Does Taking a Break Matter-Adaptations in Muscle Strength and Size Between Continuous and Periodic Resistance Training.

We aimed to compare the effects of periodic resistance training (RT) and continuous RT on muscle strength and size. Fifty-five healthy, untrained participants (age 32 ± 5 years) were randomized to periodic (PRT, n = 20 completed the study, 45% females) or continuous (CRT, n = 22 completed the study, 45% females) groups. PRT completed a 10-week RT, a 10-week detraining, and a second identical 10-week RT. CRT began with a 10-week non-RT, followed by a 20-week RT. RT included twice-weekly supervised whole-body RT sessions. Leg press (LP) and biceps curl (BC) one repetition maximum (1RM), countermovement jump (CMJ) height, muscle cross-sectional area (CSA) of vastus lateralis (VL), and biceps brachii (BB) using ultrasound imaging were measured twice at the beginning and every fifth week during the intervention. Both groups increased (p < 0.001) 1RM in LP and BC, CSA in VL and BB, and CMJ height with no differences between the groups. In PRT, 1RM in LP and BC, CSA in VL and BB, and CMJ height decreased during detraining (p < 0.05). During the first 5 weeks of retraining in PRT, increases in LP 1RM, and VL and BB CSA were greater than in CRT during Weeks 10-15 of their CRT (p < 0.01). PRT and CTR ended up in similar postintervention adaptations, as decreased muscle strength and size during detraining in PRT regained rapidly during retraining. Our results therefore suggest that trainees should not be too concerned about occasional short-term training breaks in their daily lives when it comes to lifelong strength training. Trial Registration: ClinicalTrials.gov identifier: NCT05553769.

Influence of intramuscular steroid receptor content and fiber capillarization on skeletal muscle hypertrophy.

Multiple intramuscular variables have been proposed to explain the high variability in resistance training induced muscle hypertrophy across humans. This study investigated if muscular androgen receptor (AR), estrogen receptor α (ERα) and ß (ERß) content and fiber capillarization are associated with fiber and whole-muscle hypertrophy after chronic resistance training. Male (n = 11) and female (n = 10) resistance training novices (22.1 ± 2.2 years) trained their knee extensors 3×/week for 10 weeks. Vastus lateralis biopsies were taken at baseline and post the training period to determine changes in fiber type specific cross-sectional area (CSA) and fiber capillarization by immunohistochemistry and, intramuscular AR, ERα and ERß content by Western blotting. Vastus lateralis volume was quantified by MRI-based 3D segmentation. Vastus lateralis muscle volume significantly increased over the training period (+7.22%; range: -1.82 to +18.8%, p < 0.0001) but no changes occurred in all fiber (+1.64%; range: -21 to +34%, p = 0.869), type I fiber (+1.33%; range: -24 to +41%, p = 0.952) and type II fiber CSA (+2.19%; range: -23 to +29%, p = 0.838). However, wide inter-individual ranges were found. Resistance training increased the protein expression of ERα but not ERß and AR, and the increase in ERα content was positively related to changes in fiber CSA. Only for the type II fibers, the baseline capillary-to-fiber-perimeter index was positively related to type II fiber hypertrophy but not to whole muscle responsiveness. In conclusion, an upregulation of ERα content and an adequate initial fiber capillarization may be contributing factors implicated in muscle fiber hypertrophy responsiveness after chronic resistance training.

Resistance training-induced changes in muscle proteolysis and extracellular matrix remodeling biomarkers in the untrained and trained states.

PURPOSE: Resistance training (RT) induces muscle growth at varying rates across RT phases, and evidence suggests that the muscle-molecular responses to training bouts become refined or attenuated in the trained state. This study examined how proteolysis-related biomarkers and extracellular matrix (ECM) remodeling factors respond to a bout of RT in the untrained (UT) and trained (T) state. METHODS: Participants (19 women and 19 men) underwent 10 weeks of RT. Biopsies of vastus lateralis were collected before and after (24 h) the first (UT) and last (T) sessions. Vastus lateralis cross-sectional area (CSA) was assessed before and after the experimental period. RESULTS: There were increases in muscle and type II fiber CSAs. In both the UT and T states, calpain activity was upregulated and calpain-1/-2 protein expression was downregulated from Pre to 24 h. Calpain-2 was higher in the T state. Proteasome activity and 20S proteasome protein expression were upregulated from Pre to 24 h in both the UT and T. However, proteasome activity levels were lower in the T state. The expression of poly-ubiquitinated proteins was unchanged. MMP activity was downregulated, and MMP-9 protein expression was elevated from Pre to 24 h in UT and T. Although MMP-14 protein expression was acutely unchanged, this marker was lower in T state. TIMP-1 protein levels were reduced Pre to 24 h in UT and T, while TIMP-2 protein levels were unchanged. CONCLUSION: Our results are the first to show that RT does not attenuate the acute-induced response of proteolysis and ECM remodeling-related biomarkers.

Similar muscle hypertrophy following eight weeks of resistance training to momentary muscular failure or with repetitions-in-reserve in resistance-trained individuals.

This study examined the influence of resistance training (RT) proximity-to-failure, determined by repetitions-in-reserve (RIR), on quadriceps hypertrophy and neuromuscular fatigue. Resistance-trained males (n = 12) and females (n = 6) completed an 8-week intervention involving two RT sessions per week. Lower limbs were randomised to perform the leg press and leg extension exercises either to i) momentary muscular failure (FAIL), or ii) a perceived 2-RIR and 1-RIR, respectively (RIR). Muscle thickness of the quadriceps [rectus femoris (RF) and vastus lateralis (VL)] and acute neuromuscular fatigue (i.e., repetition and lifting velocity loss) were assessed. Data was analysed with Bayesian linear mixed-effect models. Increases in quadriceps thickness (average of RF and VL) from pre- to post-intervention were similar for FAIL [0.181 cm (HDI: 0.119 to 0.243)] and RIR [0.182 cm (HDI: 0.115 to 0.247)]. Between-protocol differences in RF thickness slightly favoured RIR [-0.036 cm (HDI: -0.113 to 0.047)], but VL thickness slightly favoured FAIL [0.033 cm (HDI: -0.046 to 0.116)]. Mean volume was similar across the RT intervention between FAIL and RIR. Lifting velocity and repetition loss were consistently greater for FAIL versus RIR, with the magnitude of difference influenced by the exercise and the stage of the RT intervention.

Terminating RT sets with a close proximity-to-failure (e.g., 1- to 2-RIR) can be sufficient to promote similar hypertrophy of the quadriceps as reaching momentary muscular failure in resistance-trained individuals over eight weeks, but the overall influence of proximity-to-failure on muscle-specific hypertrophy may also depend on other factors (e.g., exercise selection, order, and subsequent musculature targeted).Due to high repetition loss (from the first to final set) when sets are terminated at momentary muscular failure, performing RT with 1- to 2-RIR allows for similar volume load and repetition volume accumulation as reaching momentary muscular failure across eight weeks, possibly influencing the overall RT stimulus achieved.Performing RT to momentary muscular failure consistently induces higher levels of acute neuromuscular fatigue versus RT performed with 1- to 2-RIR; however, improved fatigue resistance overtime may attenuate acute neuromuscular fatigue and subsequent repetition loss (but may depend on the exercise performed).

Comparative efficacy of concurrent training types on lower limb strength and muscular hypertrophy: A systematic review and network meta-analysis.

Objective: This study aims to compare, through quantitative analysis, the effectiveness of different endurance training types on increasing lower limb strength and muscle cross-sectional area (MCSA) in concurrent training. Methods: This systematic literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [PROSPERO ID: CRD42023396886]. Web of Science, SportDiscuss, Pubmed, Cochrane, and Scopus were systematically searched from their inception date to October 20, 2023. Results: A total of 40 studies (841 participants) were included in this meta-analysis. MCSA analysis showed that, compared to resistance training alone, concurrent high-intensity interval running training and resistance training and concurrent moderate-intensity continuous cycling training and resistance training were more effective (SMD = 0.15, 95% CI = -0.46 to 0.76, and SMD = 0.07, 95% CI = -0.24 to 0.38 respectively), while other modalities of concurrent training not. Lower body maximal strength analysis showed that all modalities of concurrent training were inferior to resistance training alone, but concurrent high-intensity interval training and resistance training showed an advantage in four different concurrent training modalities (SMD = -0.08, 95% CI = -0.25 to 0.08). For explosive strength, only concurrent high-intensity interval training and resistance training was superior to resistance training (SMD = 0.06, 95% CI = -0.21 to 0.33). Conclusion: Different endurance training types have an impact on the effectiveness of concurrent training, particularly on lower limb strength. Adopting high-intensity interval running as the endurance training type in concurrent training can effectively minimize the adverse effects on lower limb strength and MCSA.

Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks.

Myc is a powerful transcription factor implicated in epigenetic reprogramming, cellular plasticity, and rapid growth as well as tumorigenesis. Cancer in skeletal muscle is extremely rare despite marked and sustained Myc induction during loading-induced hypertrophy. Here, we investigated global, actively transcribed, stable, and myonucleus-specific transcriptomes following an acute hypertrophic stimulus in mouse plantaris. With these datasets, we define global and Myc-specific dynamics at the onset of mechanical overload-induced muscle fiber growth. Data collation across analyses reveals an under-appreciated role for the muscle fiber in extracellular matrix remodeling during adaptation, along with the contribution of mRNA stability to epigenetic-related transcript levels in muscle. We also identify Runx1 and Ankrd1 (Marp1) as abundant myonucleus-enriched loading-induced genes. We observed that a strong induction of cell cycle regulators including Myc occurs with mechanical overload in myonuclei. Additionally, in vivo Myc-controlled gene expression in the plantaris was defined using a genetic muscle fiber-specific doxycycline-inducible Myc-overexpression model. We determined Myc is implicated in numerous aspects of gene expression during early-phase muscle fiber growth. Specifically, brief induction of Myc protein in muscle represses Reverbα, Reverbß, and Myh2 while increasing Rpl3, recapitulating gene expression in myonuclei during acute overload. Experimental, comparative, and in silico analyses place Myc at the center of a stable and actively transcribed, loading-responsive, muscle fiber-localized regulatory hub. Collectively, our experiments are a roadmap for understanding global and Myc-mediated transcriptional networks that regulate rapid remodeling in postmitotic cells. We provide open webtools for exploring the five RNA-seq datasets as a resource to the field.

PDGF-B secreted from skeletal muscle enhances myoblast proliferation and myotube maturation via activation of the PDGFR signaling cascade.

Myokines, secreted factors from skeletal muscle, act locally on muscle cells or satellite cells, which is important in regulating muscle mass and function. Here, we found platelet-derived growth factor subunit B (PDGF-B) is constitutively secreted from muscle cells without muscle contraction. Furthermore, PDGF-B secretion increased with myoblast to myotube differentiation. To examine the role of PDGF-B as a paracrine or autocrine myokine, myoblasts or myotubes were treated with PDGF-B. As a result, myoblast proliferation was significantly enhanced via several signaling pathways. Intriguingly, myotubes treated with PDGF-B showed enhanced maturation as indicated by their increased myotube diameter, myosin heavy chain expression, and strengthened contractile force. These findings suggest that PDGF-B is constitutively secreted by myokines to enhance myoblast proliferation and myotube maturation, which may contribute to skeletal muscle regeneration.

A muscle cell-macrophage axis involving matrix metalloproteinase 14 facilitates extracellular matrix remodeling with mechanical loading.

The extracellular matrix (ECM) in skeletal muscle plays an integral role in tissue development, structural support, and force transmission. For successful adaptation to mechanical loading, remodeling processes must occur. In a large cohort of older adults, transcriptomics revealed that genes involved in ECM remodeling, including matrix metalloproteinase 14 (MMP14), were the most upregulated following 14 weeks of progressive resistance exercise training (PRT). Using single-cell RNA-seq, we identified macrophages as a source of Mmp14 in muscle following a hypertrophic exercise stimulus in mice. In vitro contractile activity in myotubes revealed that the gene encoding cytokine leukemia inhibitory factor (LIF) is robustly upregulated and can stimulate Mmp14 expression in macrophages. Functional experiments confirmed that modulation of this muscle cell-macrophage axis facilitated Type I collagen turnover. Finally, changes in LIF expression were significantly correlated with MMP14 expression in humans following 14 weeks of PRT. Our experiments reveal a mechanism whereby muscle fibers influence macrophage behavior to promote ECM remodeling in response to mechanical loading.

Muscle spasms as presenting feature of Nivelon-Nivelon-Mabile syndrome.

Hedgehog acyltransferase gene (HHAT)-associated Nivelon-Nivelon-Mabile syndrome (NNMS) is a rare genetic disorder of multiple system involvement with microcephaly, central nervous system malformations, skeletal dysplasia, and 46,XY sex reversal. Other variable and inconsistent features reported in this disorder are muscle spasms, facial dysmorphism, prenatal onset growth restriction, microphthalmia, and holoprosencephaly. This is the sixth postnatal reported patient with biallelic variants in HHAT gene, who presented with microcephaly, short stature, muscle hypertrophy, muscle spasms, and facial dysmorphism. The most prominent and presenting finding in this patient were muscle hypertrophy and muscle spasms which had a clinical response to phenytoin and acetazolamide treatment. Our report emphasizes the phenotypic variability of NNMS and further reiterates muscle spasms as an important clinical manifestation of this extremely rare condition.

Prevalence of papillary muscle hypertrophy in fabry disease.

BACKGROUND AND AIMS: Fabry disease (FD) is an X-linked genetic lysosomal disease, in which a deficit in the alpha-galactosidase A enzyme results in lysosomal build-up of globotriaosylceramide in several organs, causing cardiac, renal and cerebrovascular complications. The aim of this study was to assess the prevalence of papillary muscle hypertrophy (PMH) in patients with FD. METHODS: A group of 63 patients with FD and a positive genetic diagnosis were studied and were divided into two groups: one included 24 patients with FD and LVH and another group included 39 patients with FD and without LVH. Papillary muscles were measured from the left parasternal short axis view, defining PMH as a diastolic thickness greater than 11 mm in any diameter. RESULTS: Patients with FD and LVH had a high prevalence of anterolateral PMH (66.6%), and such prevalence was lower for the posteromedial PMH (33.3%). However, patients who had not yet developed LVH had a high prevalence of anterolateral PMH (33.3%). CONCLUSIONS: Patients with FD in the pre-clinical stage (without LVH) have a high prevalence of PMH, especially involving the anterolateral papillary muscle. This finding could be an early marker for the development of LVH, allowing to suspect the disease during its early stages, and begin enzyme replacement therapy in the appropriate patients.