Molecular Mechanisms, Therapeutic Targets and Pharmacological Interventions: An Update

Muscles are the enriched reservoir of proteins in the body. During any workout or exercise, the demand in the form of energy is essentially required by the muscle. Energy expenditure of skeletal muscle is more dependent on the type of demand. There is particular homeostasis within the body that avoid surplus energy expenditure and this prevents any muscle loss. Muscle atrophy is termed as the loss of skeletal muscle mass due to immobility, malnutrition, medications, aging, cancer cachexia, variety of injuries or diseases that impact the musculoskeletal or nervous system. Hence, atrophy within the skeletal muscle initiates further cause fatigue, pain, muscle weakness, and disability in human subjects. Therefore, starvation and reduced muscle mass further initiate numerous signaling pathways including inflammatory, antioxidant signaling, mitochondria bio-energetic failure, AMP-activated protein kinase (AMPK), Sirtuin 1(SIRT1), BDNF/TrkB/PKC, Autophagy, ubiquitin-proteasome systems, etc. Here, in this chapter, we will mention molecular mechanisms involved in therapeutic targets and available Pharmacological Interventions with the latest updates.

Clinical Relations of Sarcopenia

Sarcopenia is one of geriatric syndromes, characterized by decreased muscle mass accompanied by decreased muscle strength and/or performance. It is more prevalent with increase in age, and the prevalence depends on the criteria applied and the characteristic of the elderly. Sarcopenia has a higher risk of morbidity and mortality in elderly patients. The definition criteria of sarcopenia are still controversial, but diagnostic criteria from the Asian Working Group for Sarcopenia and the European Working Group on Sarcopenia in Older People (EWGSOP) are the most used criteria for clinical practice. Pathogenesis sarcopenia involved a multifactorial process and is divided into intrinsic and extrinsic factors. Risk factors for sarcopenia include constitutional factors, aging, lifestyle, changes in body condition, and chronic diseases. Based on that, sarcopenia is divided into primary and secondary sarcopenia. There are three stage of sarcopenia, which are pre-sarcopenia, sarcopenia, and severe sarcopenia. Nutrition and exercise are the two main pillars to manage sarcopenia.

Drugs for the Treatment of Muscle Atrophy

Muscle mass is maintained through an interplay between anabolic and catabolic pathways. The ubiquitin-proteasome system plays an important role in the proteolysis progress during skeletal muscle atrophy which can be blocked by some proteasome inhibitors. But few studies have demonstrated the ability of these inhibitors to preserve muscle mass and architecture under catabolic condition in vivo. The insulin-like growth factor-1/phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin (IGF-1/PI3K/Akt/mTOR) pathway was associated with anabolic pathways. The activation of IGF-1 causes muscle hypertrophy; however, it cannot be used as a drug target. Myostatin pathway maintains activation that can induce skeletal muscle atrophy involved with various transcriptional and genetic factors. Skeletal muscle atrophy is a debilitating consequence of multiple chronic diseases and conditions that involve starvation. It reduces treatment options and positive clinical outcomes as well as compromising quality of life and increasing morbidity and mortality. Though considerable research has been undertaken to find the drug target and the molecular mechanisms that improve skeletal muscle atrophy, no drug was approved to treat skeletal muscle atrophy. However, these years, the signaling pathways involved in muscle atrophy were clarified and some effective treatments were currently available to prevent, attenuate, or reverse muscle atrophy for experiment research.