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Physiological Reports May 2023Limited research exists examining how resistance training to failure affects applied outcomes and single motor unit characteristics in previously trained individuals.... (Randomized Controlled Trial)
Randomized Controlled Trial
Limited research exists examining how resistance training to failure affects applied outcomes and single motor unit characteristics in previously trained individuals. Herein, resistance-trained adults (24 ± 3 years old, self-reported resistance training experience was 6 ± 4 years, 11 men and 8 women) were randomly assigned to either a low-repetitions-in-reserve (RIR; i.e., training near failure, n = 10) or high-RIR (i.e., not training near failure, n = 9) group. All participants implemented progressive overload during 5 weeks where low-RIR performed squat, bench press, and deadlift twice weekly and were instructed to end each training set with 0-1 RIR. high-RIR performed identical training except for being instructed to maintain 4-6 RIR after each set. During week 6, participants performed a reduced volume-load. The following were assessed prior to and following the intervention: (i) vastus lateralis (VL) muscle cross-sectional area (mCSA) at multiple sites; (ii) squat, bench press, and deadlift one-repetition maximums (1RMs); and (iii) maximal isometric knee extensor torque and VL motor unit firing rates during an 80% maximal voluntary contraction. Although RIR was lower in the low- versus high-RIR group during the intervention (p < 0.001), total training volume did not significantly differ between groups (p = 0.222). There were main effects of time for squat, bench press, and deadlift 1RMs (all p-values < 0.05), but no significant condition × time interactions existed for these or proximal/middle/distal VL mCSA data. There were significant interactions for the slope and y-intercept of the motor unit mean firing rate versus recruitment threshold relationship. Post hoc analyses indicated low-RIR group slope values decreased and y-intercept values increased after training suggesting low-RIR training increased lower-threshold motor unit firing rates. This study provides insight into how resistance training in proximity to failure affects strength, hypertrophy, and single motor unit characteristics, and may inform those who aim to program for resistance-trained individuals.
Topics: Male; Humans; Adult; Female; Young Adult; Resistance Training; Quadriceps Muscle; Adaptation, Physiological; Acclimatization; Hypertrophy; Muscle Strength; Muscle, Skeletal
PubMed: 37144554
DOI: 10.14814/phy2.15679 -
Canadian Journal of Physiology and... Feb 2020The heart is capable of responding to stressful situations by increasing muscle mass, which is broadly defined as cardiac hypertrophy. This phenomenon minimizes... (Review)
Review
The heart is capable of responding to stressful situations by increasing muscle mass, which is broadly defined as cardiac hypertrophy. This phenomenon minimizes ventricular wall stress for the heart undergoing a greater than normal workload. At initial stages, cardiac hypertrophy is associated with normal or enhanced cardiac function and is considered to be adaptive or physiological; however, at later stages, if the stimulus is not removed, it is associated with contractile dysfunction and is termed as pathological cardiac hypertrophy. It is during physiological cardiac hypertrophy where the function of subcellular organelles, including the sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils, may be upregulated, while pathological cardiac hypertrophy is associated with downregulation of these subcellular activities. The transition of physiological cardiac hypertrophy to pathological cardiac hypertrophy may be due to the reduction in blood supply to hypertrophied myocardium as a consequence of reduced capillary density. Oxidative stress, inflammatory processes, Ca-handling abnormalities, and apoptosis in cardiomyocytes are suggested to play a critical role in the depression of contractile function during the development of pathological hypertrophy.
Topics: Animals; Apoptosis; Calcium; Cardiomegaly; Cytokines; Humans; Intracellular Space
PubMed: 31815523
DOI: 10.1139/cjpp-2019-0566 -
Fibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice.Nature Communications Mar 2023Fibroblast growth factor-18 (FGF18) has diverse organ development and damage repair roles. However, its role in cardiac homeostasis following hypertrophic stimulation...
Fibroblast growth factor-18 (FGF18) has diverse organ development and damage repair roles. However, its role in cardiac homeostasis following hypertrophic stimulation remains unknown. Here we investigate the regulation and function of the FGF18 in pressure overload (PO)-induced pathological cardiac hypertrophy. FGF18 heterozygous (Fgf18) and inducible cardiomyocyte-specific FGF18 knockout (Fgf18-CKO) male mice exposed to transverse aortic constriction (TAC) demonstrate exacerbated pathological cardiac hypertrophy with increased oxidative stress, cardiomyocyte death, fibrosis, and dysfunction. In contrast, cardiac-specific overexpression of FGF18 alleviates hypertrophy, decreased oxidative stress, attenuates cardiomyocyte apoptosis, and ameliorates fibrosis and cardiac function. Tyrosine-protein kinase FYN (FYN), the downstream factor of FGF18, was identified by bioinformatics analysis, LC-MS/MS and experiment validation. Mechanistic studies indicate that FGF18/FGFR3 promote FYN activity and expression and negatively regulate NADPH oxidase 4 (NOX4), thereby inhibiting reactive oxygen species (ROS) generation and alleviating pathological cardiac hypertrophy. This study uncovered the previously unknown cardioprotective effect of FGF18 mediated by the maintenance of redox homeostasis through the FYN/NOX4 signaling axis in male mice, suggesting a promising therapeutic target for the treatment of cardiac hypertrophy.
Topics: Male; Animals; Mice; Chromatography, Liquid; Tandem Mass Spectrometry; Fibroblast Growth Factors; Mice, Knockout; Myocytes, Cardiac; Cardiomegaly
PubMed: 36871047
DOI: 10.1038/s41467-023-36895-1 -
Biochimica Et Biophysica Acta.... Sep 2020Skeletal muscle is a dynamic tissue with two unique abilities; one is its excellent regenerative ability, due to the activity of skeletal muscle-resident stem cells... (Review)
Review
Skeletal muscle is a dynamic tissue with two unique abilities; one is its excellent regenerative ability, due to the activity of skeletal muscle-resident stem cells named muscle satellite cells (MuSCs); and the other is the adaptation of myofiber size in response to external stimulation, intrinsic factors, or physical activity, which is known as plasticity. Low physical activity and some disease conditions lead to the reduction of myofiber size, called atrophy, whereas hypertrophy refers to the increase in myofiber size induced by high physical activity or anabolic hormones/drugs. MuSCs are essential for generating new myofibers during regeneration and the increase in new myonuclei during hypertrophy; however, there has been little investigation of the molecular mechanisms underlying MuSC activation, proliferation, and differentiation during hypertrophy compared to those of regeneration. One reason is that 'degenerative damage' to myofibers during muscle injury or upon hypertrophy (especially overloaded muscle) is believed to trigger similar activation/proliferation of MuSCs. However, evidence suggests that degenerative damage of myofibers is not necessary for MuSC activation/proliferation during hypertrophy. When considering MuSC-based therapy for atrophy, including sarcopenia, it will be indispensable to elucidate MuSC behaviors in muscles that exhibit non-degenerative damage, because degenerated myofibers are not present in the atrophied muscles. In this review, we summarize recent findings concerning the relationship between MuSCs and hypertrophy, and discuss what remains to be discovered to inform the development and application of relevant treatments for muscle atrophy.
Topics: Animals; Biomarkers; Cell Proliferation; Humans; Hypertrophy; Muscle, Skeletal; Regeneration; Satellite Cells, Skeletal Muscle
PubMed: 32417255
DOI: 10.1016/j.bbamcr.2020.118742 -
The Journal of Clinical Investigation Mar 2022The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby...
The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced the accumulation of glycolytic metabolites, including l-serine, l-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.
Topics: Animals; Cardiomegaly; Citric Acid Cycle; Glucose Transporter Type 1; Glycolysis; Mice; Myocytes, Cardiac; YAP-Signaling Proteins
PubMed: 35133975
DOI: 10.1172/JCI150595 -
Circulation Research Jan 2020Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation...
RATIONALE
Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte hypertrophy during cardiac stresses. However, it remains elusive whether substrate metabolism regulates cardiomyocyte hypertrophy directly or via a secondary effect of improving cardiac energetics.
OBJECTIVE
The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes.
METHODS AND RESULTS
We cultured adult rat cardiomyocytes in a medium containing glucose and mixed-chain FAs and induced pathological hypertrophy by phenylephrine. Phenylephrine-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA, and proteins. These changes could be prevented by increasing FAO via deletion of ACC2 (acetyl-CoA-carboxylase 2) in phenylephrine-stimulated cardiomyocytes and in pressure overload-induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the antihypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in cardiomyocyte hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate, which supplied nitrogen for nucleotide synthesis during cardiomyocyte hypertrophy.
CONCLUSIONS
Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.
Topics: Acetyl-CoA Carboxylase; Animals; Aspartic Acid; Cardiomegaly; Cells, Cultured; Fatty Acids; Glucose; Male; Mice; Myocytes, Cardiac; Rats; Rats, Wistar
PubMed: 31709908
DOI: 10.1161/CIRCRESAHA.119.315483 -
International Journal of Sport... Jan 2022The acute response of muscle protein synthesis (MPS) to resistance exercise and nutrition is often used to inform recommendations for exercise programming and dietary...
The acute response of muscle protein synthesis (MPS) to resistance exercise and nutrition is often used to inform recommendations for exercise programming and dietary interventions, particularly protein nutrition, to support and enhance muscle growth with training. Those recommendations are worthwhile only if there is a predictive relationship between the acute response of MPS and subsequent muscle hypertrophy during resistance exercise training. The metabolic basis for muscle hypertrophy is the dynamic balance between the synthesis and degradation of myofibrillar proteins in muscle. There is ample evidence that the process of MPS is much more responsive to exercise and nutrition interventions than muscle protein breakdown. Thus, it is intuitively satisfying to translate the acute changes in MPS to muscle hypertrophy with training over a longer time frame. Our aim is to examine and critically evaluate the strength and nature of this relationship. Moreover, we examine the methodological and physiological factors related to measurement of MPS and changes in muscle hypertrophy that contribute to uncertainty regarding this relationship. Finally, we attempt to offer recommendations for practical and contextually relevant application of the information available from studies of the acute response of MPS to optimize muscle hypertrophy with training.
Topics: Exercise; Humans; Hypertrophy; Muscle Proteins; Muscle, Skeletal; Resistance Training
PubMed: 34697259
DOI: 10.1123/ijsnem.2021-0139 -
Journal of Applied Physiology... Sep 2019The manipulation of resistance training (RT) variables is used among athletes, recreational exercisers, and compromised populations (e.g., elderly) attempting to... (Randomized Controlled Trial)
Randomized Controlled Trial
The manipulation of resistance training (RT) variables is used among athletes, recreational exercisers, and compromised populations (e.g., elderly) attempting to potentiate muscle hypertrophy. However, it is unknown whether an individual's inherent predisposition dictates the RT-induced muscle hypertrophic response. Resistance-trained young [26 (3) y] men ( = 20) performed 8 wk unilateral RT (2 times/wk), with 1 leg randomly assigned to a standard progressive RT [control (CON)] and the contralateral leg to a variable RT (VAR; modulating exercise load, volume, contraction type, and interset rest interval). The VAR leg completed all 4 RT variations every 2 wk. Bilateral vastus lateralis cross-sectional area (CSA) was measured, pre- and post-RT and acute integrated myofibrillar protein synthesis (MyoPS) rates were assessed at rest and over 48 h following the final RT session. Muscle CSA increase was similar between CON and VAR ( > 0.05), despite higher total training volume (TTV) in VAR ( < 0.05). The 0-48-h integrated MyoPS increase postexercise was slightly greater for VAR than CON ( < 0.05). All participants were considered "responders" to RT, although none benefited to a greater extent from a specific protocol. Between-subjects variability (MyoPS, 3.30%; CSA, 37.8%) was 40-fold greater than the intrasubject (between legs) variability (MyoPS, 0.08%; CSA, 0.9%). The higher TTV and greater MyoPS response in VAR did not translate to a greater muscle hypertrophic response. Manipulating common RT variables elicited similar muscle hypertrophy than a standard progressive RT program in trained young men. Intrinsic individual factors are key determinants of the MyoPS and change in muscle CSA compared with extrinsic manipulation of common RT variables. Systematically manipulating resistance training (RT) variables during RT augments the stimulation of myofibrillar protein synthesis (MyoPS) and training volume but fails to potentiate muscle hypertrophy compared with a standard progressive RT. Any modest further MyoPS increase and higher training volumes do not reflect in a greater hypertrophic response. Between-subject variability was 40-fold greater than the variability promoted by extrinsic manipulation of RT variables, indicating that individual intrinsic factors are stronger determinants of the hypertrophic response.
Topics: Adult; Humans; Hypertrophy; Male; Muscle Proteins; Quadriceps Muscle; Resistance Training; Young Adult
PubMed: 31268828
DOI: 10.1152/japplphysiol.00350.2019 -
Biomedicine & Pharmacotherapy =... Jan 2021Qingda granule (QDG), simplified from Qingxuan Jiangya Decoction, is a well-known traditional Chinese medicine formula that has been used for decades to treat...
Qingda granule (QDG), simplified from Qingxuan Jiangya Decoction, is a well-known traditional Chinese medicine formula that has been used for decades to treat hypertension. However, the cardioprotective effects of QDG on Ang II-induced hypertension remain unknown. This study aimed to investigate the effects of QDG on hypertension-induced cardiac hypertrophy and apoptosis, as well as explore its underlying mechanisms. Mice were infused with Ang II (500 ng/kg/min) or saline solution as control, then administered oral QDG (1.145 g/kg/day) or saline for two weeks. QDG treatment attenuated the elevation in blood pressure caused by Ang II, as well as the decreased left ventricle ejection fractions and fractional shortening. Moreover, QDG treatment significantly alleviated the Ang II-induced elevation of the ratio of heart weight to tibia length, as well as cardiac injury, hypertrophy, and apoptosis. In cultured H9C2 cells stimulated with Ang II, QDG partially reversed the increase in cell surface area and number of apoptotic cells, up-regulation of hypertrophy markers ANP and BNP, and activation of caspases-9 and -3. QDG also partially reversed Ang II-induced accumulation of reactive oxygen species (ROS), depolarization of the mitochondrial membrane, release of cytochrome C, up-regulation of Bax, and decrease in levels of p-PI3K, p-AKT, and Bcl-2. These results suggest that QDG can significantly attenuate Ang II-induced hypertension, cardiac hypertrophy and apoptosis, and it may exert these effects in part by suppressing ROS production and activating the PI3K/AKT signaling pathway.
Topics: Angiotensin II; Animals; Apoptosis; Blood Pressure; Cell Line; Disease Models, Animal; Drugs, Chinese Herbal; Gene Expression Regulation; Gene Regulatory Networks; Hypertension; Hypertrophy, Left Ventricular; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Signal Transduction; Mice
PubMed: 33378940
DOI: 10.1016/j.biopha.2020.111022 -
Theranostics 2023Understanding the molecular mechanisms of deleterious cardiac remodeling is important for the development of treatments for heart failure. Recent studies have...
Understanding the molecular mechanisms of deleterious cardiac remodeling is important for the development of treatments for heart failure. Recent studies have highlighted a role of deubiquitinating enzymes in cardiac pathophysiology. In the present study, we screened for alteration of deubiquitinating enzymes in experimental models of cardiac remodeling, which indicated a potential role of OTU Domain-Containing Protein 1 (OTUD1). Wide-type or OTUD1 knockout mice with chronic angiotensin II infusion and transverse aortic constriction (TAC) were utilized to develop cardiac remodeling and heart failure. We also overexpressed OTUD1 in mouse heart with AAV9 vector to validate the function of OTUD1. LC-MS/MS analysis combined with Co-IP was used to identify the interacting proteins and substrates of OTUD1. We found that OTUD1 is elevated in mouse heart tissues following chronic angiotensin II administration. OTUD1 knockout mice were significantly protected against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis and inflammatory response. Similar results were obtained in the TAC model. Mechanistically, OTUD1 bounds to the SH2 domain of STAT3 and causes deubiquitination of STAT3. Cysteine at position 320 of OTUD1 exerts K63 deubiquitination to promote STAT3 phosphorylation and nuclear translocation, thereby increasing STAT3 activity to induce inflammatory responses, fibrosis, and hypertrophy in cardiomyocytes. Finally, OTUD1 overexpression by AAV9 vector increases Ang II-induced cardiac remodeling in mice and OTUD1-regulated responses can be inhibited by blocking STAT3. Cardiomyocyte OTUD1 promotes pathological cardiac remodeling and dysfunction by deubiquitinating STAT3. These studies have highlighted a novel role of OTUD1 in hypertensive heart failure and identified STAT3 as a target of OTUD1 in mediating these actions.
Topics: Animals; Mice; Angiotensin II; Chromatography, Liquid; Deubiquitinating Enzymes; Fibrosis; Heart Failure; Hypertrophy; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Tandem Mass Spectrometry; Ventricular Remodeling; STAT3 Transcription Factor
PubMed: 37153745
DOI: 10.7150/thno.83340