Reversing Cachexia
Posted: Tue Jul 31, 2018 9:37 pm
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Wasting of skeletal muscle is common in a number of diseases, including sepsis, severe injury, renal failure, diabetes, and cancer. Muscle atrophy leads to general muscle weakness (asthenia), impairment of normal activities, and eventually death through respiratory failure. Muscle loss is part of the syndrome of cachexia and arises through a combination of hypoanabolism, together with increased catabolism of myofibrillar proteins, particularly myosin. Cachexia affects ∼80% of patients with advanced cancers and accounts for ∼25% of deaths, but current treatments for muscle atrophy are limited. Many studies show that the ubiquitin-proteasome proteolytic pathway plays a major role in the degradation of muscle proteins during cachexia (Lecker et al., 1999). Expression of two muscle-specific ubiquitin ligases is essential for ubiquitination and subsequent degradation of myofibrillar proteins. These are MuRF1, whose substrates include myosin in muscle and troponin 1 in heart (Clarke et al., 2007), and atrogin-1/MAFbx, which targets the eukaryotic initiation factor 3 subunit 5 that induces expression of muscle structural proteins and boosts muscle growth (hypertrophy) (Lagirand-Cantaloube et al., 2008). Apoptosis may also be involved in muscle wasting, and depression of protein synthesis and stem cell quiescence are also known to lead to hypoanabolism. In this issue, Zhou et al. (2010) report the identity of a new potential therapeutic target, the activin type-2 receptor (ActRIIB), for treating muscle wasting. They show in several mouse models of cachexia that blocking ActRIIB with a decoy receptor not only counters the wasting process in skeletal muscle and heart but also is associated with increased survival.
A number of factors have been implicated in muscle wasting, including cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-6, and interferon-γ, as well as tumor factors such as proteolysis-inducing factor and glucocorticoids (Tisdale, 2009). Myostatin, a member of the TGF-β superfamily, plays an important role in glucocorticoid-induced muscle atrophy (Gilson et al., 2007). Myostatin is a negative regulator of muscle growth and, together with activin, another member of the TGF-β family, is thought to be responsible for the development of cachexia in mice lacking the hormone inhibin (which antagonizes activin action) (Matzuk et al., 1994). Both myostatin and activin bind to ActRIIB, a high-affinity activin type-2 receptor in muscle, to initiate a signaling cascade leading to increased expression of atrogin-1 and MuRF1 and increased degradation of myofibrillar proteins through the ubiquitin-proteasome pathway (Figure 1).
https://www.sciencedirect.com/science/a ... 7410008998
Main Text
Wasting of skeletal muscle is common in a number of diseases, including sepsis, severe injury, renal failure, diabetes, and cancer. Muscle atrophy leads to general muscle weakness (asthenia), impairment of normal activities, and eventually death through respiratory failure. Muscle loss is part of the syndrome of cachexia and arises through a combination of hypoanabolism, together with increased catabolism of myofibrillar proteins, particularly myosin. Cachexia affects ∼80% of patients with advanced cancers and accounts for ∼25% of deaths, but current treatments for muscle atrophy are limited. Many studies show that the ubiquitin-proteasome proteolytic pathway plays a major role in the degradation of muscle proteins during cachexia (Lecker et al., 1999). Expression of two muscle-specific ubiquitin ligases is essential for ubiquitination and subsequent degradation of myofibrillar proteins. These are MuRF1, whose substrates include myosin in muscle and troponin 1 in heart (Clarke et al., 2007), and atrogin-1/MAFbx, which targets the eukaryotic initiation factor 3 subunit 5 that induces expression of muscle structural proteins and boosts muscle growth (hypertrophy) (Lagirand-Cantaloube et al., 2008). Apoptosis may also be involved in muscle wasting, and depression of protein synthesis and stem cell quiescence are also known to lead to hypoanabolism. In this issue, Zhou et al. (2010) report the identity of a new potential therapeutic target, the activin type-2 receptor (ActRIIB), for treating muscle wasting. They show in several mouse models of cachexia that blocking ActRIIB with a decoy receptor not only counters the wasting process in skeletal muscle and heart but also is associated with increased survival.
A number of factors have been implicated in muscle wasting, including cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-6, and interferon-γ, as well as tumor factors such as proteolysis-inducing factor and glucocorticoids (Tisdale, 2009). Myostatin, a member of the TGF-β superfamily, plays an important role in glucocorticoid-induced muscle atrophy (Gilson et al., 2007). Myostatin is a negative regulator of muscle growth and, together with activin, another member of the TGF-β family, is thought to be responsible for the development of cachexia in mice lacking the hormone inhibin (which antagonizes activin action) (Matzuk et al., 1994). Both myostatin and activin bind to ActRIIB, a high-affinity activin type-2 receptor in muscle, to initiate a signaling cascade leading to increased expression of atrogin-1 and MuRF1 and increased degradation of myofibrillar proteins through the ubiquitin-proteasome pathway (Figure 1).
https://www.sciencedirect.com/science/a ... 7410008998