How Postural Muscle Senses Disuse? Early Signs and Signals

Abstract

A mammalian soleus muscle along with other “axial” muscles ensures the stability of the body under the Earth’s gravity. In rat experiments with hindlimb suspension, zero-gravity parabolic flights as well as in human dry immersion studies, a dramatic decrease in the electromyographic (EMG) activity of the soleus muscle has been repeatedly shown. Most of the motor units of the soleus muscle convert from a state of activity to a state of rest which is longer than under natural conditions. And the state of rest gradually converts to the state of disuse. This review addresses a number of metabolic events that characterize the earliest stage of the cessation of the soleus muscle contractile activity. One to three days of mechanical unloading are accompanied by energy-dependent dephosphorylation of AMPK, accumulation of the reactive oxygen species, as well as accumulation of resting myoplasmic calcium. In this transition period, a rapid rearrangement of the various signaling pathways occurs, which, primarily, results in a decrease in the rate of protein synthesis (primarily via inhibition of ribosomal biogenesis and activation of endogenous inhibitors of mRNA translation, such as GSK3β) and an increase in proteolysis (via upregulation of muscle-specific E3-ubiquitin ligases).

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.…”

“…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 ].…”

“…The contribution of NO, NOS and nitrosative stress to muscle atrophy development is still controversial, despite of the abundant evidence concerning their involvement in muscle atrophy [ 20 , 90 , 105 , 106 ]. A major point of disagreement concerns the actual availability of NO during muscle atrophy development.…”

“…Results showed an early and severe, but transient, decrease of both nNOS mRNA and protein, which returned at physiological levels after about 7 d-unloading, however, without the recovery of the physiological subcellular localization at sarcolemma [ 27 , 28 , 30 , 89 ]. Consequently, NO production in myofibers is expected to vary during unloading, because of changes in the enzyme amount, in addition to the site of production [ 20 , 105 , 113 ].…”

“…Another relevant early player involved in FoxO3 activation by unloading is the loss of AMPK activity [ 19 , 20 , 31 ]. The decrease in AMP levels, secondary to reduced/absent activity in otherwise continuously active gravitational muscles, such as the soleus muscle, leads after 12–24 h of unloading to inactive AMPK accumulation, increased ceramide concentration and p70S6K activation.…”