Periods of muscle disuse promote marked mitochondrial alterations that contribute to the impaired metabolic health and degree of atrophy in the muscle. Thus, understanding the molecular underpinnings of muscle mitochondrial decline with prolonged inactivity is of considerable interest. There are translational applications to patients subjected to limb immobilization following injury, illness-induced bed rest, neuropathies, and even microgravity. Studies in these patients, as well as on various pre-clinical rodent models have elucidated the pathways involved in mitochondrial quality control, such as mitochondrial biogenesis, mitophagy, fission and fusion, and the corresponding mitochondrial derangements that underlie the muscle atrophy that ensues from inactivity. Defective organelles display altered respiratory function concurrent with increased accumulation of reactive oxygen species, which exacerbate myofiber atrophy via degradative pathways. The preservation of muscle quality and function is critical for maintaining mobility throughout the lifespan, and for the prevention of inactivity-related diseases. Exercise training is effective in preserving muscle mass by promoting favourable mitochondrial adaptations that offset the mitochondrial dysfunction, which contributes to the declines in muscle and whole-body metabolic health. This highlights the need for further investigation of the mechanisms in which mitochondria contribute to disuse-induced atrophy, as well as the specific molecular targets that can be exploited therapeutically.

In our study, we have shown the potential of mouse skeletal muscle intermyofibrillar mitochondria to be transplanted in myoblasts and human fibroblast cells having mitochondrial DNA mutations. This resulted in an augmentation of mitochondrial dynamics and enhancement of bioenergetic profile in the host cells. Our findings suggest that mitochondria from donor skeletal muscle can be integrated into both healthy and functionally compromised host cells leading to mitochondrial structural refinement and respiratory boost.

The Mitochondrial Unfolded Protein Response (UPR^mt) is a compartment-specific mitochondrial quality control (MQC) mechanism that uses the transcription factor ATF5 to induce the expression of protective enzymes to restore mitochondrial function. Acute exercise is a stressor that has the potential to temporarily disrupt organellar protein homeostasis, however, the roles of ATF5 and the UPR^mt in maintaining basal mitochondrial content, function and exercise-induced MQC mechanisms in skeletal muscle are not known. ATF5 KO and WT mice were examined at rest or after a bout of acute endurance exercise. We measured protein content in whole muscle, nuclear, cytosolic and mitochondrial fractions, in addition to mRNA transcript levels in whole muscle. Using isolated mitochondria, we quantified rates of oxygen consumption and ROS emission to observe the effects of the absence of ATF5 on organelle function. ATF5 KO mice exhibited a larger and less functional muscle mitochondrial pool, most likely a culmination of enhanced biogenesis via increased PGC-1$\alpha$ expression, and attenuated mitophagy. The absence of ATF5 resulted in a reduction in antioxidant proteins and increases in mitochondrial ROS emission, cytosolic cytochrome c, and the expression of mitochondrial chaperones. KO muscle also displayed enhanced exercise-induced stress kinase signaling, but a blunted mitophagic and UPR^mt gene expression response, complemented by significant increases in the basal mRNA abundance and nuclear localization of ATF4. Instead of promoting its nuclear translocation, acute exercise caused the enrichment of ATF5 in mitochondrial fractions. We also identified PGC-1$\alpha$ as an additional regulator of the basal expression of UPR^mt genes. The transcription factor ATF5 retains a critical role in the maintenance of mitochondrial homeostasis and the appropriate response of muscle to acute exercise for the optimization of mitochondrial quality control.

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 field of exercise research has been expanding beyond the musculoskeletal system, with interest from industry to provide realistic models and exercise mimetics that evoke a whole body rejuvenation response. The 18th International Biochemistry of Exercise conference took place in Toronto, Canada, from May 25 to May 28, 2022, with more than 400 attendees. Here, we provide an overview of the most cutting-edge exercise-related research presented by 66 speakers, focusing on new developments in topics ranging from molecular and cellular mechanisms of exercise adaptations to exercise therapy and management of disease and aging. We also describe how the manipulation of these signaling pathways can uncover therapeutic avenues for improving human health and quality of life.

There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery–Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.