Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.

Background: Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported.

Scientific meeting report: International Biochemistry of Exercise 2022.

Exercise is one of the only nonpharmacological remedies known to counteract genetic and chronic diseases by enhancing health and improving life span. Although the many benefits of regular physical activity have been recognized for some time, the intricate and complex signaling systems triggered at the onset of exercise have only recently begun to be uncovered. Exercising muscles initiate a coordinated, multisystemic, metabolic rewiring, which is communicated to distant organs by various molecular mediators.

The influence of age, sex, and exercise on autophagy, mitophagy, and lysosome biogenesis in skeletal muscle.

Background: Aging decreases skeletal muscle mass and quality. Maintenance of healthy muscle is regulated by a balance between protein and organellar synthesis and their degradation. The autophagy-lysosome system is responsible for the selective degradation of protein aggregates and organelles, such as mitochondria (i.

Regulatory networks coordinating mitochondrial quality control in skeletal muscle.

The adaptive plasticity of mitochondria within a skeletal muscle is regulated by signals converging on a myriad of regulatory networks that operate during conditions of increased (i.e., exercise) and decreased (inactivity, disuse) energy requirements.

Measurement of Protein Import Capacity of Skeletal Muscle Mitochondria.

Mitochondria are key metabolic and regulatory organelles that determine the energy supply as well as the overall health of the cell. In skeletal muscle, mitochondria exist in a series of complex morphologies, ranging from small oval organelles to a broad, reticulum-like network. Understanding how the mitochondrial reticulum expands and develops in response to diverse stimuli such as alterations in energy demand has long been a topic of research.

Mitochondrial protein import and UPR in skeletal muscle remodeling and adaptation.

The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the organelle are encoded in the nucleus, synthesized in the cytosol, and imported into mitochondria via the protein import machinery, which permit the entry of proteins to expand the mitochondrial network. Once inside, proteins undergo a maturation and folding process brought about by enzymes comprising the unfolded protein response (UPR).

p53 regulates skeletal muscle mitophagy and mitochondrial quality control following denervation-induced muscle disuse.

Persistent inactivity promotes skeletal muscle atrophy, marked by mitochondrial aberrations that affect strength, mobility, and metabolic health leading to the advancement of disease. Mitochondrial quality control (MQC) pathways include biogenesis (synthesis), mitophagy/lysosomal turnover, and the mitochondrial unfolded protein response, which serve to maintain an optimal organelle network. Tumor suppressor p53 has been implicated in regulating muscle mitochondria in response to cellular stress; however, its role in the context of muscle disuse has yet to be explored, and whether p53 is necessary for MQC remains unclear.

Human cardiac ischemia-reperfusion injury: Blunted stress response with age.

Background And Aim: Autophagy is a cytoprotective recycling mechanism, capable of digesting dysfunctional cellular components, and this process is associated with pro-survival outcomes. Autophagy may decline in the aging myocardium, thereby contributing to cardiac dysfunction. However, it remains to be established how autophagy responds to ischemia-reperfusion stress with age.

Exercise Is Muscle Mitochondrial Medicine.

Exercise stimulates the biogenesis of mitochondria in muscle. Some literature supports the use of pharmaceuticals to enhance mitochondria as a substitute for exercise. We provide evidence that exercise rejuvenates mitochondrial function, thereby augmenting muscle health with age, in disease, and in the absence of cellular regulators.

The intersection of exercise and aging on mitochondrial protein quality control.

Skeletal muscle quality and quantity are negatively impacted with age. Part of this decline in function can be attributed to alterations in mitochondrial turnover, and in the mechanisms that regulate mitochondrial homeostasis. Protein quality control within the mitochondria relies on a number of interconnected processes, namely the mitochondrial unfolded protein response (UPR), protein import and mitophagy.

Exercise is mitochondrial medicine for muscle.

Mitochondria are vital organelles that provide energy for muscle function. When these organelles become dysfunctional, they produce less energy as well as excessive levels of reactive oxygen species which can trigger muscle atrophy, weakness and loss of endurance. In this review, molecular evidence is provided to show that exercise serves as a useful therapeutic countermeasure to overcome mitochondrial dysfunction, even when key regulators of organelle biogenesis are absent.

Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging.

Mitochondria are critical organelles responsible for regulating the metabolic status of skeletal muscle. These organelles exhibit remarkable plasticity by adapting their volume, structure, and function in response to chronic exercise, disuse, aging, and disease. A single bout of exercise initiates signaling to provoke increases in mitochondrial biogenesis, balanced by the onset of organelle turnover carried out by the mitophagy pathway.

Effect of Tim23 knockdown in vivo on mitochondrial protein import and retrograde signaling to the UPR in muscle.

The mitochondrial unfolded protein response (UPR) is a protein quality control mechanism that strives to achieve proteostasis in the face of misfolded proteins. Because of the reliance of mitochondria on both the nuclear and mitochondrial genomes, a perturbation of the coordination of these genomes results in a mitonuclear imbalance in which holoenzymes are unable to assume mature stoichiometry and thereby activates the UPR. Thus, we sought to perturb this genomic coordination by using a systemic antisense oligonucleotide (in vivo morpholino) targeted to translocase of the inner membrane channel subunit 23 (Tim23), the major channel of the inner membrane.

Function of specialized regulatory proteins and signaling pathways in exercise-induced muscle mitochondrial biogenesis.

Skeletal muscle mitochondrial content and function are regulated by a number of specialized molecular pathways that remain to be fully defined. Although a number of proteins have been identified to be important for the maintenance of mitochondria in quiescent muscle, the requirement for these appears to decrease with the activation of multiple overlapping signaling events that are triggered by exercise. This makes exercise a valuable therapeutic tool for the treatment of mitochondrially based metabolic disorders.

Chronology of UPR activation in skeletal muscle adaptations to chronic contractile activity.

The mitochondrial and endoplasmic reticulum unfolded protein responses (UPR(mt) and UPR(ER)) are important for cellular homeostasis during stimulus-induced increases in protein synthesis. Exercise triggers the synthesis of mitochondrial proteins, regulated in part by peroxisome proliferator activator receptor-γ coactivator 1α (PGC-1α). To investigate the role of the UPR in exercise-induced adaptations, we subjected rats to 3 h of chronic contractile activity (CCA) for 1, 2, 3, 5, or 7 days followed by 3 h of recovery.