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Skeletal muscle wasting is the hallmark pathophysiological adaptation to unloading or disuse that demonstrates the dependency on frequent mechanical stimulation (e.g. muscle activation and subsequent loading) for homeostasis of normally load-bearing muscles. In the absence of mitigation strategies, no mammalian organism is resistant to muscle atrophy driven by unloading. Given the profound impact of unloading-induced muscle wasting on physical capacity, metabolic health and immune function; mitigation strategies during unloading and/or augmentation approaches during recovery have broad healthcare implications in settings of bed-bound hospitalization, cast immobilization and spaceflight. This topical review aims to: (1) provide a succinct, state-of-the-field summary of seminal and recent findings regarding the mechanisms of unloading-induced skeletal muscle wasting; (2) discuss unsuccessful vs. promising mitigation and recovery augmentation strategies; and (3) identify knowledge gaps ripe for future research. We focus on the rapid muscle atrophy driven by relatively short-term mechanical unloading/disuse, which is in many ways mechanistically distinct from both hypermetabolic muscle wasting and denervation-induced muscle atrophy. By restricting this discussion to mechanical unloading during which all components of the nervous system remain intact (e.g. without denervation models), mechanical loading requiring motor and sensory neural circuits in muscle remain viable targets for both mitigation and recovery augmentation. We emphasize findings in humans with comparative discussions of studies in rodents which enable elaboration of key mechanisms. We also discuss what is currently known about the effects of age and sex as biological factors, and both are highlighted as knowledge gaps and novel future directions due to limited research.
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Resistance training (RT) remains the most effective treatment for age-related declines in muscle mass. However, many older adults experience attenuated muscle hypertrophy in response to RT when compared with younger adults. This may be attributed to underlying molecular processes that are dysregulated by aging and exacerbated by improperly prescribed RT weekly volume, intensity, and/or frequency doses. MicroRNAs (miRNAs) are key epigenetic regulators that impact signaling pathways and protein expression within cells, are dynamic and responsive to exercise stimuli, and are often dysregulated in diseases. In this study, we used untargeted miRNA-seq to examine miRNA in skeletal muscle and serum-derived exosomes of older adults (n = 18, 11 M/7 F, 66 ± 1 yr) who underwent three times per wk RT for 30 wk [e.g., high intensity three times/wk (HHH, n = 9) or alternating high-low-high (HLH) intensity (n = 9)], after a standardized 4-wk washin. Within each tissue, miRNAs were clustered into modules based on pairwise correlation using weighted gene correlation network analysis (WGCNA). Modules were tested for association with the magnitude of RT-induced thigh lean mass (TLM) change [as measured by dual-energy X-ray absorptiometry (DXA)]. Although no modules were unique to training dose, we identified miRNA modules in skeletal muscle associated with TLM gains irrespective of exercise dose. Using miRNA-target interactions, we analyzed key miRNAs in significant modules for their potential regulatory involvement in biological pathways. Findings point toward potential miRNAs that may be informative biomarkers and could also be evaluated as potential therapeutic targets as an adjuvant to RT to maximize skeletal muscle mass accrual in older adults.NEW & NOTEWORTHY In this work, we identified a set of microRNAs correlated with thigh lean mass gains in a group of older adults. To our knowledge, this is the first time these microRNAs have been identified as novel predictive biomarkers correlating with lean mass gains in aging adults. As biomarkers, these may help interventionalists identify older individuals that are positively responding to an exercise intervention.
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MicroRNAs , Músculo Esquelético , Treinamento Resistido , Coxa da Perna , Humanos , Treinamento Resistido/métodos , MicroRNAs/genética , MicroRNAs/metabolismo , Masculino , Idoso , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Feminino , Envelhecimento/fisiologia , Envelhecimento/genética , Exossomos/metabolismo , Pessoa de Meia-Idade , Composição Corporal/fisiologiaRESUMO
The progression of osteoarthritis of the hip to its end stage and ultimately to total hip arthroplasty (THA) is complex; the multifactorial pathophysiology involves myriad collaborating tissues in and around the diseased joint. We have named the heightened state of periarticular muscle inflammation at the time of surgery "muscle inflammation susceptibility" (MuIS) because it is distinct from systemic inflammation. In this review article, we discuss how MuIS and heightened atrophy-associated signaling in the periarticular skeletal muscles may contribute to reduced muscle mass, impaired muscle quality (ie, through fibrosis), and a muscle microenvironment that challenges regenerative capacity and thus functional recovery from THA. We also review directions for future research that should advance understanding of the key determinants of precision for optimized success of THA for each individual.
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Traumatic spinal cord injury (SCI) results in wide-ranging cellular and systemic dysfunction in the acute and chronic time frames after the injury. Chronic SCI has well-described secondary medical consequences while acute SCI has unique metabolic challenges as a result of physical trauma, in-patient recovery and other post-operative outcomes. Here, we used high resolution mass spectrometry approaches to describe the circulating lipidomic and metabolomic signatures using blood serum from mice 7 d after a complete SCI. Additionally, we probed whether the aporphine alkaloid, boldine, was able to prevent SCI-induced changes observed using these 'omics platforms'. We found that SCI resulted in large-scale changes to the circulating lipidome but minimal changes in the metabolome, with boldine able to reverse or attenuate SCI-induced changes in the abundance of 50 lipids. Multiomic integration using xMWAS demonstrated unique network structures and community memberships across the groups.
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Aporfinas , Traumatismos da Medula Espinal , Masculino , Animais , Camundongos , Lipidômica , Soro , Aporfinas/farmacologia , Aporfinas/uso terapêuticoRESUMO
Membrane channels such as those formed by connexins (Cx) and P2X7 receptors (P2X7R) are permeable to calcium ions and other small molecules such as adenosine triphosphate (ATP) and glutamate. Release of ATP and glutamate through these channels is a key mechanism driving tissue response to traumas such as spinal cord injury (SCI). Boldine, an alkaloid isolated from the Chilean boldo tree, blocks both Cx and Panx1 hemichannels (HCs). To test if boldine could improve function after SCI, boldine or vehicle was administered to treat mice with a moderate severity contusion-induced SCI. Boldine led to greater spared white matter and increased locomotor function as determined by the Basso Mouse Scale and horizontal ladder rung walk tests. Boldine treatment reduced immunostaining for markers of activated microglia (Iba1) and astrocytic (GFAP) markers while increasing that for axon growth and neuroplasticity (GAP-43). Cell culture studies demonstrated that boldine blocked glial HC, specifically Cx26 and Cx30, in cultured astrocytes and blocked calcium entry through activated P2X7R. RT-qPCR studies showed that boldine treatment reduced expression of the chemokine Ccl2, cytokine IL-6 and microglial gene CD68, while increasing expression of the neurotransmission genes Snap25 and Grin2b, and Gap-43. Bulk RNA sequencing revealed that boldine modulated a large number of genes involved in neurotransmission in spinal cord tissue just caudal from the lesion epicenter at 14 days after SCI. Numbers of genes regulated by boldine was much lower at 28 days after injury. These results indicate that boldine treatment ameliorates injury and spares tissue to increase locomotor function.
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Spinal cord injury (SCI) results in rapid muscle loss. Exogenous molecular interventions to slow muscle atrophy after SCI have been relatively ineffective and require the search for novel therapeutic targets. Connexin hemichannels (CxHCs) allow nonselective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising preclinical results in slowing atrophy during sepsis and restoring muscle function in dysferlinopathy. We administered 50 mg/kg/day of boldine to spinal cord transected mice beginning 3 days post-injury. Tissue was collected 7 and 28 days post-SCI and the gastrocnemius was used for multiomics profiling. Boldine did not prevent body or muscle mass loss but attenuated SCI-induced changes in the abundance of the amino acids proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 days post-SCI. SCI resulted in the differential expression of â¼7,700 and â¼2,000 genes at 7 and 28 days, respectively, compared with Sham controls. Pathway enrichment of these genes highlighted ribosome biogenesis at 7 days and translation and oxidative phosphorylation at both timepoints. Boldine altered the expression of â¼150 genes at 7 days and â¼110 genes at 28 days post-SCI. Pathway enrichment of these genes indicated a potential role for boldine in suppressing protein ubiquitination and degradation at the 7-day timepoint. Methylation analyses showed minimal differences between groups. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it attenuated some SCI-induced changes across the metabolome and transcriptome.NEW & NOTEWORTHY This is the first study to describe the multiome of skeletal muscle paralyzed by a spinal cord injury (SCI) in mice across the acute and subacute timeframe after injury. We show large-scale changes in the metabolome and transcriptome at 7 days post-injury compared with 28 days. Furthermore, we show that the alkaloid boldine was able to prevent SCI-induced changes in muscle glucose and free amino acid levels at 7 days, but not 28 days, after SCI.
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Aporfinas , Traumatismos da Medula Espinal , Camundongos , Animais , Multiômica , Músculo Esquelético/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Aporfinas/metabolismo , Aporfinas/farmacologia , Glucose/metabolismoRESUMO
Angiotensin (1-7) [Ang (1-7)] is an active heptapeptide of the noncanonical arm of the renin-angiotensin system that modulates molecular signaling pathways associated with vascular and cellular inflammation, vasoconstriction, and fibrosis. Preclinical evidence suggests that Ang (1-7) is a promising therapeutic target that may ameliorate physical and cognitive function in late life. However, treatment pharmacodynamics limits its clinical applicability. Therefore, this study explored the underlying mechanisms altered by a genetically modified probiotic (GMP) that expresses Ang (1-7) combined with and without exercise training in an aging male rat model as a potential adjunct strategy to exercise training to counteract the decline of physical and cognitive function. We evaluated cross-tissue (prefrontal cortex, hippocampus, colon, liver, and skeletal muscle) multi-omics responses. After 12 wk of intervention, the 16S mRNA microbiome analysis revealed a main effect of probiotic treatment within- and between groups. The probiotic treatment enhanced α diversity (Inverse Simpson (F[2,56] = 4.44; P = 0.02); Shannon-Wiener (F[2,56] = 4.27; P = 0.02)) and ß-diversity (F[2,56] = 2.66; P = 0.01) among rats receiving our GMP. The analysis of microbes' composition revealed three genera altered by our GMP (Enterorhabdus, Muribaculaceae unclassified, and Faecalitalea). The mRNA multi-tissue data analysis showed that our combined intervention upregulated neuroremodeling pathways on prefrontal cortex (i.e., 140 genes), inflammation gene expression in the liver (i.e., 63 genes), and circadian rhythm signaling on skeletal muscle. Finally, the integrative network analysis detected different communities of tightly (|r| > 0.8 and P < 0.05) correlated metabolites, genera, and genes in these tissues.NEW & NOTEWORTHY This manuscript uses a multiomics approach (i.e., microbiome, metabolomics, and transcriptomics) to explore the underlying mechanisms driven by a genetically modified probiotic (GMP) designed to express angiotensin (1-7) combined with moderate exercise training in an aged male rat model. After 12 wk of intervention, our findings suggest that our GMP enhanced gut microbial diversity while exercise training altered the transcriptional response in relevant neuroremodeling genes, inflammation, and circadian rhythm signaling pathways in an aging animal model.
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Multiômica , Condicionamento Físico Animal , Ratos , Animais , Masculino , Condicionamento Físico Animal/fisiologia , Sistema Renina-Angiotensina/fisiologia , InflamaçãoRESUMO
Acute exercise elicits dynamic transcriptional changes that, when repeated, form the fundamental basis of health, resilience, and performance adaptations. While moderate-intensity endurance training combined with conventional resistance training (traditional, TRAD) is often prescribed and recommended by public health guidance, high-intensity training combining maximal-effort intervals with intensive, limited-rest resistance training is a time-efficient alternative that may be used tactically (HITT) to confer similar benefits. Mechanisms of action of these distinct stimuli are incompletely characterized and have not been directly compared. We assessed transcriptome-wide responses in skeletal muscle and circulating extracellular vesicles (EVs) to a single exercise bout in young adults randomized to TRAD (n = 21, 12 M/9 F, 22 ± 3 yr) or HITT (n = 19, 11 M/8 F, 22 ± 2 yr). Next-generation sequencing captured small, long, and circular RNA in muscle and EVs. Analysis identified differentially expressed transcripts (|log2FC|>1, FDR ≤ 0.05) immediately (h0, EVs only), h3, and h24 postexercise within and between exercise protocols. In aaddition, all apparently responsive transcripts (FDR < 0.2) underwent singular value decomposition to summarize data structures into latent variables (LVs) to deconvolve molecular expression circuits and interregulatory relationships. LVs were compared across time and exercise protocol. TRAD, a longer but less intense stimulus, generally elicited a stronger transcriptional response than HITT, but considerable overlap and key differences existed. Findings reveal shared and unique molecular responses to the exercise stimuli and lay groundwork toward establishing relationships between protein-coding genes and lesser-understood transcripts that serve regulatory roles following exercise. Future work should advance the understanding of these circuits and whether they repeat in other populations or following other types of exercise/stress.NEW & NOTEWORTHY We examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.
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Treinamento Resistido , Transcriptoma , Humanos , Adulto Jovem , Transcriptoma/genética , Exercício Físico/fisiologia , Perfilação da Expressão Gênica , Músculo Esquelético/metabolismoRESUMO
ABSTRACT: Pearson, JR, Moodie, N, Stout, KW, Hawkins, WC, Matuszek, M, Graham, ZA, Siedlik, JA, Vardiman, JP, and Gallagher, PM. Similar responses in the Akt/protein kinase B (PKB) signaling pathway after different lower-body exercise volumes in recreationally active men. J Strength Cond Res 37(5): 1034-1041, 2023-This project examined the differences between a single set (SS) compared to multiple sets (MS) of resistance exercise on the Akt/protein kinase B (PKB) signaling pathway, the expression of insulin-like growth factor-1 ( IGF-1 ), and the receptor for IGF -1 ( IGF-1R ) to better understand the types of resistance training protocols that are most beneficial in stimulating the muscle hypertrophic response. Sixteen healthy men were randomly selected into 2 groups of 8. Subjects in each group received 3 biopsies: (a) before exercise, (b) 15 minutes postexercise, and (c) 180 minutes postexercise. Subjects in the SS group performed 1 set of leg press to failure at 80% of their predetermined 1 repetition maximum (1RM). Subjects in the MS group performed 2 sets of 10 repetitions and 1 set to failure at 80% of their predetermined 1RM, with 3 minutes of rest between each set. Our results indicated no group × time interactions in the concentration of Akt signaling proteins. Furthermore, there were no group × time interactions in IGF-1 or IGF-1R expression. However, phosphorylated 4E-binding protein 1 levels increased 150% from pre to 180 minutes post ( p = 0.005). In addition, there was a significantly greater increase in IGF-1R expression in the SS group compared with the MS group (7.99 ± 10.07 vs. 4.41 ± 6.28; p = 0.026). Collectively, we found that a SS of resistance training evokes a similar acute Akt/PKB pathway response as MS in recreationally active men.
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Proteínas Proto-Oncogênicas c-akt , Treinamento Resistido , Humanos , Masculino , Exercício Físico , Fator de Crescimento Insulin-Like I , Músculo Esquelético/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Treinamento Resistido/métodos , Transdução de SinaisRESUMO
Membrane channels such as connexins (Cx), pannexins (Panx) and P2X 7 receptors (P2X 7 R) are permeable to calcium ions and other small molecules such as ATP and glutamate. Release of ATP and glutamate through these channels is a key mechanism driving tissue response to traumas such as spinal cord injury (SCI). Boldine, an alkaloid isolated from the Chilean boldo tree, blocks both Cx hemichannels (HC) and Panx. To test if boldine could improve function after SCI, boldine or vehicle was administered to treat mice with a moderate severity contusion-induced SCI. Boldine led to greater spared white matter and increased locomotor function as determined by the Basso Mouse Scale and horizontal ladder rung walk tests. Boldine treatment reduced immunostaining for markers of activated microglia (Iba1) and astrocytic (GFAP) markers while increasing that for axon growth and neuroplasticity (GAP-43). Cell culture studies demonstrated that boldine blocked glial HC, specifically Cx26 and Cx30, in cultured astrocytes and blocked calcium entry through activated P2X 7 R. RT-qPCR studies showed that boldine treatment reduced expression of the chemokine Ccl2, cytokine IL-6 and microglial gene CD68, while increasing expression of the neurotransmission genes Snap25 and Grin2b, and Gap-43. Bulk RNA sequencing (of the spinal cord revealed that boldine modulated a large number of genes involved in neurotransmission in in spinal cord tissue just below the lesion epicenter at 14 days after SCI. Numbers of genes regulated by boldine was much lower at 28 days after injury. These results indicate that boldine treatment ameliorates injury and spares tissue to increase locomotor function.
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AIM: This study was primarily aimed at assessing the effect that specific periodontal phenotypical characteristics have on alveolar ridge remodelling after tooth extraction. MATERIALS AND METHODS: Patients in need of extraction of a non-molar maxillary tooth were enrolled. Baseline phenotypical characteristics (i.e., mid-facial and mid-palatal soft tissue and bone thickness, and supracrestal soft tissue height [STH]) were recorded upon extraction. A set of clinical, digital imaging (linear and volumetric), and patient-reported outcomes were assessed over a 14-week healing period. RESULTS: A total of 78 subjects were screened. Forty-two subjects completed the study. Linear and volumetric bone changes, as well as vertical linear soft tissue and alveolar ridge volume (soft tissue contour) variations, were indicative of a marked dimensional reduction of the alveolar ridge over time. Horizontal facial and palatal soft tissue thickness gain was observed. Thin facial bone (≤1 mm) upon extraction, compared with thick facial bone (>1 mm), was associated with greater linear horizontal (-4.57 ± 2.31 mm vs. -2.17 ± 1.65 mm, p = .003) and vertical mid-facial (-0.95 ± 0.67 mm vs. -4.08 ± 3.52 mm, p < 0.001) and mid-palatal (-2.03 ± 2.08 mm vs. -1.12 ± 0.99 mm, p = 0.027) bone loss, as well as greater total (-34% ± 10% vs. 15% ± 6%, p < 0.001), facial (-51% ± 19% vs. 28% ± 18%, p = 0.040), and palatal bone volume reduction (-26% ± 14% vs. -8% ± 10%, p < 0.001). Aside from alveolar bone thickness, STH was also found to be a predictor of alveolar ridge resorption since this variable was directly correlated with bone volume reduction. Patient-reported discomfort scores progressively decreased over time, and the mean satisfaction upon study completion was 94.5 ± 0.83 out of 100. CONCLUSIONS: Alveolar ridge remodelling is a physiological phenomenon that occurs after tooth extraction. Post-extraction alveolar ridge atrophy is more marked on the facio-coronal aspect. These dimensional changes are more pronounced in sites exhibiting a thin facial bone phenotype (Clinicaltrials.gov NCT02668289).
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Perda do Osso Alveolar , Aumento do Rebordo Alveolar , Humanos , Alvéolo Dental/cirurgia , Processo Alveolar/diagnóstico por imagem , Processo Alveolar/cirurgia , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/etiologia , Assistência Odontológica , Extração Dentária , Fenótipo , Aumento do Rebordo Alveolar/métodosRESUMO
The ability of individuals with end-stage osteoarthritis (OA) to functionally recover from total joint arthroplasty is highly inconsistent. The molecular mechanisms driving this heterogeneity have yet to be elucidated. Furthermore, OA disproportionately impacts females, suggesting a need for identifying female-specific therapeutic targets. We profiled the skeletal muscle transcriptome in females with end-stage OA (n = 20) undergoing total knee or hip arthroplasty using RNA-Seq. Single-gene differential expression (DE) analyses tested for DE genes between skeletal muscle overlaying the surgical (SX) joint and muscle from the contralateral (CTRL) leg. Network analyses were performed using Pathway-Level Information ExtractoR (PLIER) to summarize genes into latent variables (LVs), i.e., gene circuits, and link them to biological pathways. LV differences in SX versus CTRL muscle and across sources of muscle tissue (vastus medialis, vastus lateralis, or tensor fascia latae) were determined with ANOVA. Linear models tested for associations between LVs and muscle phenotype on the SX side (inflammation, function, and integrity). DE analysis revealed 360 DE genes (|Log2 fold-difference| ≥ 1, FDR ≤ 0.05) between the SX and CTRL limbs, many associated with inflammation and lipid metabolism. PLIER analyses revealed circuits associated with protein degradation and fibro-adipogenic cell gene expression. Muscle inflammation and function were linked to an LV associated with endothelial cell gene expression highlighting a potential regulatory role of endothelial cells within skeletal muscle. These findings may provide insight into potential therapeutic targets to improve OA rehabilitation before and/or following total joint replacement.
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Artroplastia de Quadril , Artroplastia do Joelho , Osteoartrite , Feminino , Humanos , Células Endoteliais , Articulação do Joelho , Osteoartrite/genética , Músculo EsqueléticoRESUMO
Spinal cord injury (SCI) leads to major reductions in function, independent living, and quality of life. Disuse and paralysis from SCI leads to rapid muscle atrophy, with chronic muscle loss likely playing a role in the development of the secondary metabolic disorders often seen in those with SCI. Muscle disuse is associated with mitochondrial dysfunction. Previous evidence has suggested targeting the mitochondria with the tetrapeptide SS-31 is beneficial for muscle health in preclinical models that lead to mitochondrial dysfunction, such as cast immobilization or burn injury. We gave young male mice a sham (n = 8) or 65 kdyne thoracic contusion SCI with (n = 9) or without (n = 9) daily administration of 5.0 mg/kg SS-31. Hindlimb muscle mass and muscle bundle respiration were measured at 7 days post-SCI and molecular targets were investigated using immunoblotting, RT-qPCR, and metabolomics. SS-31 did not preserve body mass or hindlimb muscle mass 7 days post-SCI. SS-31 had no effect on soleus or plantaris muscle bundle respiration. SCI was associated with elevated levels of protein carbonylation, led to reduced protein expression of activated DRP1 and reductions in markers of mitochondrial fusion. SS-31 administration did result in reduced total DRP1 expression, as well as greater expression of inhibited DRP1. Gene expression of proinflammatory cytokines and their receptors were largely stable across groups, although SS-31 treatment led to greater mRNA expression of IL1B, TNF, and TNFRSF12A. In summation, SS-31 was not an efficacious treatment acutely after a moderate thoracic contusion SCI in young male mice.
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Contusões , Traumatismos da Medula Espinal , Animais , Contusões/complicações , Masculino , Camundongos , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/prevenção & controle , Qualidade de Vida , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismoRESUMO
NEW FINDINGS: What is the central question of this study? Do Notch, Numb and Numb-like expression change in human skeletal muscle after exercise-induced muscle damage? What are the main finding and its importance? Notch gene expression trends toward an increase in response to an acute bout of exercise-induced muscle damage, while Numb and Numb-like expression does not change. These results suggest that human skeletal muscle response to exercise-induced muscle damage is dynamic and may differ from Drosophila and rodent models. Furthermore, the timing of muscle biopsies, training status and muscle damage protocols should be considered. ABSTRACT: This investigation examined changes in the gene and protein expression of Notch, Numb and Numb-like (Numbl) in human skeletal muscle after an acute bout of eccentric exercise-induced muscle damage. Twelve recreationally active male subjects participated in this study. These individuals completed seven sets of 10 repetitions of eccentric leg extension at 120% of one-repetition max with 2 min of rest period between sets. Four muscle biopsies of the vastus lateralis were collected: before exercise (Pre), and 3 h, 2 days and 5 days post-muscle damage. Biopsy samples were used to probe Notch, Numb and Numbl utilizing western blot and RT-qPCR techniques. The results were analysed using a one-way repeated-measures ANOVA. Notch1 mRNA expression trended toward a significant increase from Pre to 2 days post-muscle damage from baseline measures (P = 0.087), while Numb (P = 0.804) and Numbl (P = 0.480) expression was unaltered post-muscle damage. There were no significant differences in protein expression post-muscle damage for any of the proteins. These results suggest that exercise-induced muscle damage, via eccentric exercise, slightly elevates Notch1 mRNA expression.
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Exercício Físico , Proteínas de Membrana , Proteínas do Tecido Nervoso , Receptor Notch1 , Exercício Físico/fisiologia , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Músculo Quadríceps/fisiologia , RNA Mensageiro/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , DescansoRESUMO
This study aimed to characterize the effects of laparotomy on postoperative physical function and skeletal muscle gene expression in male C57BL/6N mice at 3, 20, and 24 months of age to investigate late-life vulnerability and resiliency to acute surgical stress. Pre and postoperative physical functioning was assessed by forelimb grip strength on postoperative day (POD) 1 and 3 and motor coordination on POD 2 and 4. Laparotomy-induced an age-associated postoperative decline in forelimb grip strength that was the greatest in the oldest mice. While motor coordination declined with increasing age at baseline, it was unaffected by laparotomy. Baseline physical function as stratified by motor coordination performance (low functioning vs high functioning) in 24-month-old mice did not differentially affect postlaparotomy reduction in grip strength. RNA sequencing of soleus muscles showed that laparotomy-induced age-associated differential gene expression and canonical pathway activation with the greatest effects in the youngest mice. Examples of such age-associated, metabolically important pathways that were only activated in the youngest mice after laparotomy included oxidative phosphorylation and NRF2-mediated oxidative stress response. Analysis of lipid mediators in serum and gastrocnemius muscle showed alterations in profiles during aging and confirmed an association between such changes and functional status in gastrocnemius muscle. These findings demonstrate a mouse model of laparotomy which recapitulated some features of postoperative skeletal muscle decline in older adults, and identified age-associated, laparotomy-induced molecular signatures in skeletal muscles. Future research can build upon this model to study molecular mechanisms of late-life vulnerability and resiliency to acute surgical stress.
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Complicações Cognitivas Pós-Operatórias , Transcriptoma , Animais , Modelos Animais de Doenças , Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , RNA/metabolismo , Análise de Sequência de RNARESUMO
Skeletal muscle develops in a manner directly related to its innervating motor neuron. The formation of the neuromuscular junction (NMJ) is a well-described process that is coordinated to allow for efficient communication between the central nervous system and muscle for muscle contraction and movement. Some of the major mediators of NMJ formation, like muscle-specific kinase, agrin and laminin, have been thoroughly described but there are other important proteins that have an integral role in muscle health that have also been associated with proper NMJ integrity and fiber health and function. This mini-review focuses on integrins, connexin hemichannels and ephrins and their relationship with the NMJin regulating muscle health.
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Conexinas/metabolismo , Efrinas/metabolismo , Integrinas/metabolismo , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/fisiologia , Junção Neuromuscular/fisiologia , Animais , HumanosRESUMO
Skeletal muscle atrophy is a hallmark of severe spinal cord injury (SCI) that is precipitated by the neural insult and paralysis. Additionally, other factors may influence muscle loss, including systemic inflammation, low testosterone, low insulin-like growth factor (IGF)-1, and high-dose glucocorticoid treatment. The signaling cascades that drive SCI-induced muscle loss are common among most forms of disuse atrophy and include ubiquitin-proteasome signaling and others. However, differing magnitudes and patterns of atrophic signals exist after SCI versus other disuse conditions and are accompanied by endogenous inhibition of IGF-1/PI3K/Akt signaling, which combine to produce exceedingly rapid atrophy. Several well-established anabolic agents, including androgens and myostatin inhibitors, display diminished ability to prevent SCI-induced atrophy, while ursolic acid and ß2-agonists more effectively attenuate muscle loss. Strategies combining physical rehabilitation regimens to reload the paralyzed limbs with drugs targeting the underlying molecular pathways hold the greatest potential to improve muscle recovery after severe SCI.
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Atrofia Muscular/prevenção & controle , Preparações Farmacêuticas , Traumatismos da Medula Espinal , Humanos , Músculo Esquelético/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologiaRESUMO
Skeletal muscle is the most abundant tissue in healthy individuals and it has important roles in health beyond voluntary movement. The overall mass and energy requirements of skeletal muscle require it to be metabolically active and flexible to multiple energy substrates. The tissue has evolved to be largely load dependent and it readily adapts in a number of positive ways to repetitive overload, such as various forms of exercise training. However, unloading from extended bed rest and/or metabolic derangements in response to trauma, acute illness, or severe pathology, commonly results in rapid muscle wasting. Decline in muscle mass contributes to multimorbidity, reduces function, and exerts a substantial, negative impact on the quality of life. The principal mechanisms controlling muscle mass have been well described and these cellular processes are intricately regulated by exercise. Accordingly, exercise has shown great promise and efficacy in preventing or slowing muscle wasting through changes in molecular physiology, organelle function, cell signaling pathways, and epigenetic regulation. In this review, we focus on the role of exercise in altering the molecular landscape of skeletal muscle in a manner that improves or maintains its health and function in the presence of unloading or disease.epigenetics; exercise; muscle wasting; resistance training; skeletal muscle.
Assuntos
Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/prevenção & controle , Biossíntese de Proteínas , Treinamento Resistido/métodos , Sepse/metabolismo , Adaptação Fisiológica , Animais , Repouso em Cama/efeitos adversos , Queimaduras/genética , Queimaduras/metabolismo , Queimaduras/patologia , Queimaduras/reabilitação , Epigênese Genética , Humanos , Denervação Muscular/reabilitação , Proteínas Musculares/biossíntese , Músculo Esquelético/lesões , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Proteólise , Qualidade de Vida/psicologia , Comportamento Sedentário , Sepse/microbiologia , Sepse/patologia , Sepse/reabilitação , Transdução de Sinais , Ausência de Peso/efeitos adversosRESUMO
Spinal cord injury (SCI) results in dysregulation of carbohydrate and lipid metabolism; the underlying cellular and physiological mechanisms remain unclear. Fibroblast growth factor 21 (FGF21) is a circulating protein primarily secreted by the liver that lowers blood glucose levels, corrects abnormal lipid profiles, and mitigates non-alcoholic fatty liver disease. FGF21 acts via activating FGF receptor 1 and ß-klotho in adipose tissue and stimulating release of adiponectin from adipose tissue which in turn signals in the liver and skeletal muscle. We examined FGF21/adiponectin signaling after spinal cord transection in mice fed a high fat diet (HFD) or a standard mouse chow. Tissues were collected at 84 days after spinal cord transection or a sham SCI surgery. SCI reduced serum FGF21 levels and hepatic FGF21 expression, as well as ß-klotho and FGF receptor-1 (FGFR1) mRNA expression in adipose tissue. SCI also reduced serum levels and adipose tissue mRNA expression of adiponectin and leptin, two major adipokines. In addition, SCI suppressed hepatic type 2 adiponectin receptor (AdipoR2) mRNA expression and PPARα activation in the liver. Post-SCI mice fed a HFD had further suppression of serum FGF21 levels and hepatic FGF21 expression. Elevated serum free fatty acid (FFA) levels after HFD feeding were observed in post-SCI mice but not in sham-mice, suggesting defective FFA uptake after SCI. Moreover, after SCI several genes that are implicated in insulin's action had reduced expression in tissues of interest. These findings suggest that downregulated FGF21/adiponectin signaling and impaired responsiveness of adipose tissues to FGF21 may, at least in part, contribute to the overall picture of metabolic dysfunction after SCI.
Assuntos
Tecido Adiposo/patologia , Fatores de Crescimento de Fibroblastos/sangue , Inflamação/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Traumatismos da Medula Espinal/complicações , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica , Inflamação/sangue , Inflamação/etiologia , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Transdução de SinaisRESUMO
Spinal cord injury (SCI) leads to rapid muscle atrophy due to paralysis/paresis and subsequent disuse. SS-31 is a mitochondrial-targeting peptide that has shown efficacy in protecting skeletal muscle mass and function in non-SCI models of muscle wasting. We aimed to determine if SS-31 could prevent muscle loss after SCI. Male C57BL/6 mice aged 9 weeks underwent sham surgery or 50 kdyne contusion SCI and were administered daily injections of vehicle or 5 mg/kg SS-31 for 14 d. Both SCI groups had sustained losses in body mass compared to Sham animals and ~10% reductions in gastrocnemius, plantaris and tibialis anterior muscle mass after SCI with no clear effect of SS-31. Measurements of protein synthesis in the soleus and plantaris were similar among all groups. mRNA expression of atrophy-associated proinflammatory cytokines was also similar among all groups. There was elevation in MYH7 mRNA and a statistical reduction in MYH2 mRNA expression in the SCI+SS-31 animals compared to Sham animals. There was an SCI-induced reduction in mRNA expression of the E3 ligase FBXO32 (MAFbx), but no effect of SS-31. In summary, a 50 kdyne contusion SCI was able to reduce body mass but was not associated with substantial muscle atrophy or alterations in gene expression profiles associated with muscle health and function 14 d post-injury. SS-31 was not associated with protection against SCI-related changes in body or muscle mass, protein synthesis or gene expression in hindlimb muscles.