of a mitochondrion in an autophagic vacuole (autophagosome) and the hydrolytic degradation of its cargo by fusion with lysosomes (autolysosome) [69].
Profound alterations in mitochondrial fusion and fission proteins have been associated with many age‐related conditions, including obesity, neurodegenerative diseases, cardiovascular diseases, type 2 diabetes, and age‐related sarcopenia. Although most of these studies were conducted in animal models, they suggest that a dysregulation of mitochondrial dynamics may play an important role in age‐related sarcopenia and other age‐related chronic conditions in humans [70]. Supporting evidence for this theory comes from the fact that “in vivo;” genetic manipulations of proteins involved in fission accelerated muscle mass decline with aging in mice, while the inhibition of fission prevented sarcopenia. Moreover, overexpression of dynamin‐like 120‐kDa protein (OPA1), an essential protein for mitochondrial fusion, is protective against denervation‐induced muscle atrophy [71]. The expression of mitochondrial fusion and fission proteins is reduced during aging in human skeletal muscle [72, 73]. Reduced levels of Mitofusin‐2 (MFN‐2), an outer membrane mitochondrial protein essential for mitochondrial fusion, have been found in sarcopenic older individuals, as compared to age‐matched controls [74]. In addition, several lines of research suggest that autophagy becomes defective with aging, including some evidence regarding human skeletal muscle.
The persistence of severely damaged mitochondria jeopardizes attempts to replace them with new, healthy mitochondria. Stressed mitochondria also release non‐methylated mtDNA and formyl peptides, that are viewed by the immune system as damage‐associated molecular patterns (DAMPs) and detected by Toll Like Receptor 9 (TLR9) and the NLRP3 Inflammasome [75]. The latter triggers caspase‐1 activation and the production of interleukin (IL)‐1β and IL‐18 [76]. A third recently identified pro‐inflammatory pathway triggered by released mtDNA involves recognition by the cytosolic sensor cGAS, which activates the adaptor protein STING and the kinase TKB1 leading to the production of type 1 interferons (IFN) [77]. Based on these mechanisms, it is not surprising that the slow, continuous release of mtDNA has been proposed as one of the potential causes of the pro‐inflammatory state that is often recognized in older individuals and that has been associated with cardiovascular diseases and other chronic diseases [78]. Interestingly, a pro‐inflammatory state witnessed by high levels of pro‐inflammatory markers, such as C‐Reactive protein and, less consistently, IL‐6, has been associated with age‐related sarcopenia and recognized as a risk factor for sarcopenia development [79]. It has been suggested that this association is caused by inflammatory mediators that enhance protein catabolism and inhibit protein synthesis, both directly and through interference with the production and biological activity of Insulin‐like growth factor‐1 [75]. However, the specific mechanism by which inflammation affects muscle protein metabolism has not been fully elucidated. Attempts to prevent or reverse sarcopenia by reducing inflammation in humans have had limited success [79].
Apoptosis
There is strong evidence that apoptosis, the process of programmed cell death, plays a primary role in the pathogenesis of the age‐associated decline of muscle mass and strength. Studies that compared skeletal muscle tissues from younger and older rats reported high levels of apoptosis and connected the degree of muscle mass decline with the severity of apoptotic DNA fragmentation [80–82]. Apoptosis appears to be more frequent among type II fibers, possibly consequently to the higher susceptibility to TNF‐alpha signaling pathway. In skeletal muscle fibers, apoptosis can be induced either through a mitochondria‐independent or a mitochondria‐dependent mechanism, and it is not established which one of these pathways contributes to the accelerated decline of muscle mass and strength that eventually leads to sarcopenia. In mitochondria, apoptosis is initiated by mitochondrial matrix accumulation of Ca2+ which leads to the opening of the permeability transition pore (MPTP), a large non‐selective channel in the inner mitochondrial membrane. The opening of the MPTP increases concentrations of ROS, elicits membrane depolarization, and releases cytochrome c into the cytosol, activating the apoptotic program through a number of intermediate steps, including the activation of caspase‐9 and caspase‐3. Apoptosis includes reorganization of the cytoskeleton, arrest of cell replication, fragmentation of the nuclear membrane and the DNA, and eventually cell death. There is some but not concluding evidence that the threshold for apoptosis activation is increased in aging skeletal muscle, especially in humans. Further research is needed in this field. Interestingly, exercise and dietary restriction attenuate apoptosis with aging [81, 82]. Targeting apoptosis might be an effective intervention to counteract age‐related muscle wasting. However, more mechanistic studies are required before potentially effective treatment strategies can be developed.
Mitochondrial proteostasis mechanisms
A perfectly tuned control of the protein concentrations, quality control and recycling are essential for mitochondrial health. Such control is exerted by the ubiquitin‐proteasome system (UPS) and the autophagy–lysosome system. These catabolic mechanisms are modulated by the AMP‐Kinase and the FOXO transcription factor family, which inhibit MTORC1, the master regulator of protein synthesis and degradation. However, whether a dysregulation of this proteostasis mechanism leads to accelerated protein breakdown with aging, which results into a decline of muscle mass, or rather a failure of protein synthesis in replacing the degraded proteins, is currently unknown. Discovery proteomics studies in human muscle have found a substantial underrepresentation of ribosome proteins with older age, suggesting that failing anabolic mechanisms are probably preponderant. On the other hand, studies have found UPS‐related proteins and transcription factors overrepresented in quadriceps muscle of older compared with younger persons, while other studies failed to confirm these findings [83, 84]. In conclusion, the mitochondrial quality control system is altered at several levels. While it is reasonable to hypothesize that proteostatis mechanisms play an important role in the maintenance of integrity and efficiency of mitochondria, whether these mechanisms eventually contribute to age‐related sarcopenia remains unknown.
ARE AGE‐RELATED CHANGES IN MITOCHONDRIAL FUNCTION AT THE ROOT OF SARCOPENIA?
As outlined above, there is substantial evidence that mitochondrial function in skeletal muscle declines with aging, and that such decline has important functional consequences on mobility performance. We have examined several possible causes of mitochondrial dysfunction with aging, including a progressive decline of physical function, oxidative stress, anabolic resistance, accumulation of somatic mutations, and alterations of mitochondrial quality control mechanisms including proteostasis, fusion/fission, and mitophagy. Although we have attempted to be as comprehensive as possible in our review of the literature, we are fully aware that this chapter cannot exhaustively explore the enormous literature on the complex relationship between mitochondria, skeletal muscle, and aging. For example, there is evidence that part of the decline in muscle strength with aging is due to a dysfunction of neurological control, both at the central and the peripheral level, and mitochondrial aging presumably contributes to this important cause of sarcopenia. Since the neurological prospective to sarcopenia is addressed in another chapter of this book, we are confident that these aspects will not be ignored in this publication.
Importantly, many of the changes in mitochondria described in this chapter occur in the majority of aging individuals, and not only in those who develop sarcopenia. Thus, the question remains: “Is mitochondrial dysfunction the cause of age‐related sarcopenia?”. In spite of extensive and sophisticated research in this field, a solid answer to such question is still lacking. Of course, if the age‐associated changes described here are overt, the structure and function of mitochondria would be damaged with serious consequences on muscle oxidative capacity, and ultimately on the anatomic integrity and the ability to produce contractile force. Arguably, the lack of success in this field is due to a substantial disagreement between investigators about the appropriate definition of sarcopenia (also addressed elsewhere in this book), and to the fact that few studies have performed muscle biopsies in older persons affected by sarcopenia, which is often associated with poor health status and disability. As mentioned earlier, perhaps the best evidence that sarcopenia is associated with poor mitochondrial function is a gene expression