Cellular homeostasis requires tight coordination between nucleus and mitochondria, organelles that each possesses their own genomes. Disrupted mitonuclear communication has been found to be implicated in many aging processes. However, little is known about mitonuclear signaling regulator in sarcopenia which is a major contributor to the risk of poor health-related quality of life, disability, and premature death in older people. High-temperature requirement protein A2 (HtrA2/Omi) is a mitochondrial protease and plays an important role in mitochondrial proteostasis. HtrA2mnd2(-/-) mice harboring protease-deficient HtrA2/Omi Ser276Cys missense mutants exhibit premature aging phenotype. Additionally, HtrA2/Omi has been established as a signaling regulator in nervous system and tumors. We therefore asked whether HtrA2/Omi participates in mitonuclear signaling regulation in muscle degeneration. Using motor functional, histological, and molecular biological methods, we characterized the phenotype of HtrA2mnd2(-/-) muscle. Furthermore, we isolated the gastrocnemius muscle of HtrA2mnd2(-/-) mice and determined expression of genes in mitochondrial unfolded protein response (UPRmt ), mitohormesis, electron transport chain (ETC), and mitochondrial biogenesis. Here, we showed that HtrA2/Omi protease deficiency induced denervation-independent skeletal muscle degeneration with sarcopenia phenotypes. Despite mitochondrial hypofunction, upregulation of UPRmt and mitohormesis-related genes and elevated total reactive oxygen species (ROS) production were not observed in HtrA2mnd2(-/-) mice, contrary to previous assumptions that loss of protease activity of HtrA2/Omi would lead to mitochondrial dysfunction as a result of proteostasis disturbance and ROS burst. Instead, we showed that HtrA2/Omi protease deficiency results in different changes between the expression of nuclear DNA- and mitochondrial DNA-encoded ETC subunits, which is in consistent with their transcription factors, nuclear respiratory factors 1 and 2, and coactivator peroxisome proliferator-activated receptor γ coactivator 1α. These results reveal that loss of HtrA2/Omi protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia. The novel mechanistic insights may be of importance in developing new therapeutic strategies for sarcopenia.

Loss of high-temperature requirement protein A2 protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia.

BACKGROUND
As people age, physical impairments may have a deleterious role in skeletal muscles. Sarcopenia Clinical Practice Guidelines 2017 and the European Working Group on Sarcopenia in older people are two organizations that have published essential guidelines on the definition of "sarcopenia". Sarcopenia is a geriatric syndrome, characterized by skeletal muscle mass degeneration brought on by ageing, which lowers muscular function and quality. Moreover, sarcopenia can be classified as primary or age-associated sarcopenia and secondary sarcopenia. Also, secondary sarcopenia occurs when other diseases such as diabetes, obesity, cancer, cirrhosis, myocardial failure, chronic obstructive pulmonary disease, and inflammatory bowel disease also contribute to muscle loss. Furthermore, sarcopenia is linked with a high risk of negative outcomes, considering a gradual reduction in physical mobility, poor balance, and increased fracture risks which ultimately leads to poor quality of life.


OBJECTIVE
In this comprehensive review, we have elaborated on the pathophysiology, and various signaling pathways linked with sarcopenia. Also, discussed are the preclinical models and current interventional therapeutics to treat muscle wasting in older patients.


CONCLUSION
In a nutshell, a comprehensive description of the pathophysiology, mechanisms, animal models, and interventions of sarcopenia. We also shed light on pharmacotherapeutics present in clinical trials which are being developed as potential therapeutic options for wasting diseases. Thus, this review could fill in the knowledge gaps regarding sarcopenia-related muscle loss and muscle quality for both researchers and clinicians.

A Comprehensive Review of Essential Aspects of Molecular Pathophysiological Mechanisms with Emerging Interventions for Sarcopenia in Older People.

Characterisation of nf‐kb activation in regenerating fibres of old mice

Effect of denervation on redox‐regulation in skeletal muscle

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Characterisation of nf‐kb activation in regenerating fibres of old mice

Effect of denervation on redox‐regulation in skeletal muscle