Muscle wasting in disease: molecular mechanisms and promising therapies

Abstract

Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting.

Circulating Activin A predicts survival in cancer patients

“…In humans, elevated ActA levels have been observed in several inflammatory diseases, such as septicemia35 or acute distress syndrome,36 and are associated with the severity of the disease and poor prognosis. Neoplastic process is associated with systemic inflammation, mediated by several cytokines such as IL‐1β, IL‐6, TNFα, and ActA 37, 38. High levels of inflammation, characterized by elevated CRP and low albumin levels are clearly associated with body weight loss and reduced survival in cancer patients 37.…”

Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment

“…[111][112][113][114][115][116] In detail, it has been demonstrated that physical exercise significantly decreases GSK-3β activity in rat skeletal muscle within 10 min of exercise and remained depressed with 30 and 60 min of exercise. 110 In the following part current treatment substances discoveries will be listed (see for detailed therapies 117,118 ).…”

Coordinate regulation of autophagy and the ubiquitin proteasome system by MTOR

“…5,16 This marked loss of muscle mass is a characteristic cellular response in specific muscles upon denervation or disuse and occurs systemically in muscles upon fasting, cancer cachexia, and other chronic illnesses. 17 Unlike the rapid changes induced by MTORC1, the profound loss of muscle protein seen in these catabolic states is a transcriptional adaptive response involving induction by FOXO transcription factors of a set of atrophy-related genes ("atrogenes"), including several specific ubiquitin ligases and many autophagy genes. 17 This FOXO-mediated stimulation of protein breakdown requires hours or days to cause prolonged activation of these 2 degradative systems.…”

“…17 Unlike the rapid changes induced by MTORC1, the profound loss of muscle protein seen in these catabolic states is a transcriptional adaptive response involving induction by FOXO transcription factors of a set of atrophy-related genes ("atrogenes"), including several specific ubiquitin ligases and many autophagy genes. 17 This FOXO-mediated stimulation of protein breakdown requires hours or days to cause prolonged activation of these 2 degradative systems. Thus, MTOR inhibition and FOXO activation appear to have complementary roles upon starvation in vivo or in disease, and probably function sequentially to activate overall proteolysis and to enable the nutrient-deficient organism to mobilize essential amino acids from cell proteins and even from extracellular proteins 18 for gluconeogenesis, energy production, or for synthesis of essential proteins.…”