Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial network is essential for ...cardiovascular function and adaptation to pathological stressors. Mitochondria undergo fission or fusion in response to various environmental cues, and these dynamic changes are vital for mitochondrial function and health. In particular, mitochondrial fission is closely coordinated with the cell cycle and is linked to changes in mitochondrial respiration and membrane permeability. Another key function of fission is the segregation of damaged mitochondrial components for degradation by mitochondrial autophagy (mitophagy). Mitochondrial fission is induced by the large GTPase dynamin-related protein 1 (DRP1) and is subject to sophisticated regulation. Activation requires various post-translational modifications of DRP1, actin polymerization and the involvement of other organelles such as the endoplasmic reticulum, Golgi apparatus and lysosomes. A decrease in mitochondrial fusion can also shift the balance towards mitochondrial fission. Although mitochondrial fission is necessary for cellular homeostasis, this process is often aberrantly activated in cardiovascular disease. Indeed, strong evidence exists that abnormal mitochondrial fission directly contributes to disease development. In this Review, we compare the physiological and pathophysiological roles of mitochondrial fission and discuss the therapeutic potential of preventing excessive mitochondrial fission in the heart and vasculature.
The primary aim of this study was to compare rating of perceived exertion (RPE) values measuring repetitions in reserve (RIR) at particular intensities of 1 repetition maximum (RM) in experienced ...(ES) and novice squatters (NS). Furthermore, this investigation compared average velocity between ES and NS at the same intensities. Twenty-nine individuals (24.0 ± 3.4 years) performed a 1RM squat followed by a single repetition with loads corresponding to 60, 75, and 90% of 1RM and an 8-repetition set at 70% 1RM. Average velocity was recorded at 60, 75, and 90% 1RM and on the first and last repetitions of the 8-repetition set. Subjects reported an RPE value that corresponded to an RIR value (RPE-10 = 0-RIR, RPE-9 = 1-RIR, and so forth). Subjects were assigned to one of the 2 groups: (a) ES (n = 15, training age: 5.2 ± 3.5 years) and (b) NS (n = 14, training age: 0.4 ± 0.6 years). The mean of the average velocities for ES was slower (p ≤ 0.05) than NS at 100% and 90% 1RM. However, there were no differences (p > 0.05) between groups at 60, 75%, or for the first and eighth repetitions at 70% 1RM. In addition, ES recorded greater RPE at 1RM than NS (p = 0.023). In ES, there was a strong inverse relationship between average velocity and RPE at all percentages (r = -0.88, p < 0.001), and a strong inverse correlation in NS between average velocity and RPE at all intensities (r = -0.77, p = 0.001). Our findings demonstrate an inverse relationship between average velocity and RPE/RIR. Experienced squatter group exhibited slower average velocity and higher RPE at 1RM than NS, signaling greater efficiency at high intensities. The RIR-based RPE scale is a practical method to regulate daily training load and provide feedback during a 1RM test.
Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are ...normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.
Mitochondrial dysfunction is a hallmark of cardiac pathophysiology. Defects in mitochondrial performance disrupt contractile function, overwhelm myocytes with reactive oxygen species (ROS), and ...transform these cellular powerhouses into pro-death organelles. Thus, quality control (QC) pathways aimed at identifying and removing damaged mitochondrial proteins, components, or entire mitochondria are crucial processes in post-mitotic cells such as cardiac myocytes. Almost all of the mitochondrial proteins are encoded by the nuclear genome and the trafficking of these nuclear-encoded proteins necessitates significant cross-talk with the cytosolic protein QC machinery to ensure that only functional proteins are delivered to the mitochondria. Within the organelle, mitochondria contain their own protein QC system consisting of chaperones and proteases. This system represents another level of QC to promote mitochondrial protein folding and prevent aggregation. If this system is overwhelmed, a conserved transcriptional response known as the mitochondrial unfolded protein response is activated to increase the expression of proteins involved in restoring mitochondrial proteostasis. If the mitochondrion is beyond repair, the entire organelle must be removed before it becomes cytotoxic and causes cellular damage. Recent evidence has also uncovered mitochondria as participants in cytosolic protein QC where misfolded cytosolic proteins can be imported and degraded inside mitochondria. However, this process also places increased pressure on mitochondrial QC pathways to ensure that the imported proteins do not cause mitochondrial dysfunction. This review is focused on discussing the pathways involved in regulating mitochondrial QC and their relationship to cellular proteostasis and mitochondrial health in the heart.
Although recent advances in the treatment of acute coronary heart disease have reduced mortality rates, few therapeutic strategies exist to mitigate the progressive loss of cardiac function that ...manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, Nrf2) is a transcriptional regulator that is known to confer transient myocardial cytoprotection following acute ischemic insult; however, its sustained activation paradoxically causes a reductive environment characterized by excessive antioxidant activity. We previously identified a subset of 16 microRNAs (miRNA) significantly diminished in Nrf2-ablated (Nrf2
) mouse hearts, leading to the hypothesis that increasing levels of Nrf2 activation augments miRNA induction and post-transcriptional dysregulation. Here, we report the identification of distinct miRNA signatures (i.e. "reductomiRs") associated with Nrf2 overexpression in a cardiac-specific and constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing low (TgL) and high (TgH) levels. We also found several Nrf2 dose-responsive miRNAs harboring proximal antioxidant response elements (AREs), implicating these "reductomiRs" as putative meditators of Nrf2-dependent post-transcriptional regulation. Analysis of mRNA-sequencing identified a complex network of miRNAs and effector mRNAs encoding known pathological hallmarks of cardiac stress-response. Altogether, these data support Nrf2 as a putative regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation to understand the relationship between myocardial reductive stress and cardiac pathophysiology.
The overarching aim of this study was to compare volume-equated high-repetition daily undulating periodization (DUPHR) versus a low-repetition daily undulating periodization (DUPLR) program for ...muscle performance. Sixteen college-aged (23 ± 3 years) resistance-trained males were counterbalanced into 2 groups: (i) DUPHR (n = 8), with a weekly training order of 12 repetitions (Day 1), 10 repetitions (Day 2), and 8 repetitions (Day 3); and (ii) DUPLR (n = 8), with a weekly training order of 6 repetitions (Day 1), 4 repetitions (Day 2), and 2 repetitions (Day 3). Both groups trained 3 times/week for 8 weeks on nonconsecutive days, with pre- and post-training testing during weeks 1 and 8. Participants performed only squat and bench press exercises each session. Changes in one-repetition maximum (1RM) strength, muscle thickness (MT), and muscular endurance (ME) were assessed. Both groups significantly increased 1RM strength for both squat and bench press (p < 0.01), and no group differences existed (p > 0.05). Similarly, both groups experienced significant increases in chest, lateral quadriceps distal, and anterior quadriceps MT (p < 0.05), but no change was present in either group for lateral quadriceps mid MT (p < 0.05). No group differences were discovered for changes in MT (p > 0.05). ME did not significantly change in the squat or bench press for either group (p > 0.05); however, for squat ME, a moderate effect size was observed for DUPHR (0.57) versus a trivial effect size for DUPLR (0.17). Our findings suggest that in previously trained males, training volume is a significant contributor to strength and hypertrophy adaptations, which occur independently of specific repetition ranges.
The degradation of macromolecules and organelles by the process of autophagy is critical for cellular homeostasis and is often compromised during aging and disease. Beclin1 and Beclin2 are implicated ...in autophagy induction, and these homologs share a high degree of amino acid sequence similarity but have divergent N-terminal regions. Here, we investigated the functions of the Beclin homologs in regulating autophagy and mitophagy, a specialized form of autophagy that targets mitochondria. Both Beclin homologs contributed to autophagosome formation, but a mechanism of autophagosome formation independent of either Beclin homolog occurred in response to starvation or mitochondrial damage. Mitophagy was compromised only in Beclin1-deficient HeLa cells and mouse embryonic fibroblasts because of defective autophagosomal engulfment of mitochondria, and the function of Beclin1 in mitophagy required the phosphorylation of the conserved Ser
residue by the kinase Ulk1. Mitochondria-ER-associated membranes (MAMs) are important sites of autophagosome formation during mitophagy, and Beclin1, but not Beclin2 or a Beclin1 mutant that could not be phosphorylated at Ser
, localized to MAMs during mitophagy. Our findings establish a regulatory role for Beclin1 in selective mitophagy by initiating autophagosome formation adjacent to mitochondria, a function facilitated by Ulk1-mediated phosphorylation of Ser
in its distinct N-terminal region.
Nuclear factor, erythroid 2 like 2 (Nfe2l2 or Nrf2), is a transcription factor that protects cells by maintaining a homeostatic redox state during stress. The constitutive expression of Nrf2 ...(CaNrf2-TG) was previously shown to be pathological to the heart over time. We tested a hypothesis that the cardiac-specific expression of full length Nrf2 (mNrf2-TG) would moderately increase the basal antioxidant defense, triggering a pro-reductive environment leading to adaptive cardiac remodeling. Transgenic and non-transgenic (NTG) mice at 7−8 months of age were used to analyze the myocardial transcriptome, structure, and function. Next generation sequencing (NGS) for RNA profiling and qPCR-based validation of the NGS data, myocardial redox levels, and imaging (echocardiography) were performed. Transcriptomic analysis revealed that out of 14,665 identified mRNAs, 680 were differently expressed (DEG) in TG hearts. Of 680 DEGs, 429 were upregulated and 251 were downregulated significantly (FC > 2.0, p < 0.05). Gene set enrichment analysis revealed that the top altered pathways were (a) Nrf2 signaling, (b) glutathione metabolism and (c) ROS scavenging. A comparative analysis of the glutathione redox state in the hearts demonstrated significant differences between pro-reductive vs. hyper-reductive conditions (233 ± 36.7 and 380 ± 68.7 vs. 139 ± 8.6 µM/mg protein in mNrf2-TG and CaNrf2-TG vs. NTG). Genes involved in fetal development, hypertrophy, cytoskeletal rearrangement, histone deacetylases (HDACs), and GATA transcription factors were moderately increased in mNrf2-TG compared to CaNrf2-TG. Non-invasive echocardiography analysis revealed an increase in systolic function (ejection fraction) in mNrf2-TG, suggesting an adaptation, as opposed to pathological remodeling in CaNrf2-TG mice experiencing a hyper-reductive stress, leading to reduced survival (40% at 60 weeks). The effects of excess Nrf2-driven antioxidant transcriptome revealed a pro-reductive condition in the myocardium leading to an adaptive cardiac remodeling. While pre-conditioning the myocardial redox with excess antioxidants (i.e., pro-reductive state) could be beneficial against oxidative stress, a chronic pro-reductive environment in the myocardium might transition the adaptation to pathological remodeling.
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