Signaling Pathways That Control Muscle Mass

Abstract

<jats:p>The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as well as overall health and wellbeing. This tissue’s remarkable ability to rapidly and effectively adapt to changing environmental cues is a double-edged sword. Physiological adaptations that are beneficial throughout life become maladaptive during atrophic conditions. The atrophic program can be activated by mechanical, oxidative, and energetic distress, and is influenced by the availability of nutrients, growth factors, and cytokines. Largely governed by a transcription-dependent mechanism, this program impinges on multiple protein networks including various organelles as well as biosynthetic and quality control systems. Although modulating muscle function to prevent and treat disease is an enticing concept that has intrigued research teams for decades, a lack of thorough understanding of the molecular mechanisms and signaling pathways that control muscle mass, in addition to poor transferability of findings from rodents to humans, has obstructed efforts to develop effective treatments. Here, we review the progress made in unraveling the molecular mechanisms responsible for the regulation of muscle mass, as this continues to be an intensive area of research.</jats:p>

MuRF1/TRIM63, Master Regulator of Muscle Mass

“…The NF-kB signaling pathway is activated upon inflammatory cytokine production and the MuRF1 promoter possesses NF-kB binding sites ( Figure 2 b), which enables a direct induction of MuRF1 mRNA production [ 67 ] ( Figure 2 a). The NF-kB pathway can be activated by TNFα or by TWEAK, two inflammatory cytokines that potently induce MuRF1 overexpression and muscle atrophy [ 68 , 69 ]. As an example of the respective roles of the different transcription factors, the NF-kB sites were required for disuse atrophy-linked MuRF1 expression, while FoxO sites were dispensable [ 67 ].…”

Master Regulators of Muscle Atrophy: Role of Costamere Components

“…Experimental models reproducing different conditions leading to muscle atrophy have been developed and used to identify master regulators of atrophy by means of either pharmacological or genetic tools. Detailed reviews about the involvement of regulators of muscle transcription, protein synthesis, and anabolic signaling pathways, protein catabolism and autophagy have recently appeared [ 19 , 20 , 21 , 22 ]. Therefore, we would largely refer to these contributions and limit our presentation to knowledge concerning evidence of the major or partial involvement of these regulators with costamere components in different atrophy conditions.…”

“…FoxOs (FoxO1, FoxO3, FoxO4) are involved in most types of muscle atrophy, since the inhibition or genetic deletion of multiple FoxOs completely prevented its development induced by fasting, glucocorticoid treatment and diabetes [ 19 ]. Conversely, deletion of all FoxO family members only attenuated muscle atrophy induced by limb immobilization and reduced, but not abolished, the expression of major atrogenes, such as MuRF1 and MAFbx/Atrogin-1 [ 23 ].…”

“…Furthermore, FoxO apparently does not play a role in sarcopenia development [ 25 ], whereas MuRF1 is involved, since its deletion resulted in the maintenance of muscle mass with age [ 26 ]. Activation of FoxO3 results from the deregulation of several signaling systems, among which are: (i) the derangement of the Insulin Receptor (IR) cascade [ 19 ], (ii) the untethering of the neuronal isoform of Nitric Oxide Synthase (nNOS) from sarcolemma [ 27 , 28 , 29 , 30 ], (iii) the excessive activation of the anabolic response [ 19 ], possibly secondary to the lack of AMPK activation [ 20 , 31 ], (iv) the loss of FoxO3 inhibitory posttranslational modifications by means of HDAC1 [ 32 , 33 ], and (v) the inhibition of Akt activity by Smad2/3 signaling [ 34 ].…”

Mineral Deficiencies: A Root Cause for Reduced Longevity in Mammals

“…According to previous reports, high potassium levels depolarizes smooth muscle cells that opens up voltage gated calcium channels resulting in entry of calcium ions inside the cells thereby leading to activation of smooth muscle contraction [44] The role of potassium in muscle contraction shown in Figure 2b. It had reported that activation of mTORC1 signalling correlated with decline in muscle mass [45,46] activated mTORC1induces oxidative stress that leads to protein degradation, autophagy and necrosis showing an aged phenotype [47]. The signalling pathway connecting potassium deficiency and ageing shown in…”