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**Figure 1.** Experimental models used to study skeletal muscle wasting. (A) Microgravity devices: the life sciences BION satellite launched on a Soyuz rocket, and the actual orbital International Space Station (ISS) including the Mice Drawer System (MDS). (B) Models of cell line experiments with induction of muscle wasting. (C) Ground-based animal models of muscle wasting and aging including transgenic mice, denervated, and hindlimb-unloaded rodents. (D) Human experimental protocols for studies on muscle deconditioning: bed rest with a –6° head-down tilt position, dry immersion, and a model of unilateral lower-limb suspension, with a left shoe with a thick sole and the shoulder strap running around the foot and ankle to unload the right foot.

**Figure 2.** Histological analysis of IMAT accumulation induced in the glycerol model of skeletal-muscle regeneration in mice. (A) A histological longitudinal paraffin-embedded muscle section, stained with hematoxylin-eosin-saffron, 21 days after intramuscular injection of glycerol into the murine tibialis anterior muscle. (B) A histological transversal paraffin-embedded muscle section, 21 days after intramuscular injection of glycerol into the tibialis anterior (labeling with an anti-PDGFRα antibody).

**Figure 3.** G6PDH-linked mechanisms possibly involved in sarcopenia. Aging is associated with a decrease in G6PDH activity and/or protein content in skeletal muscle; this change may lead to less active synthesis of NADPH and ribose 5-phosphate. The decrease in NADPH levels should impair the redox status, and this event may exacerbate apoptosis and proteolysis and impede muscle regeneration and protein synthesis. The downregulation of ribose 5-phosphate may impair DNA and mRNA synthesis, thus decreasing protein synthesis. All these mechanisms may lead to sarcopenia.
Special Issue: “Molecular Aspects of Sarcopenia and Frailty”

<table><caption>Table 1. A summary of methods for assessment of muscle mass, muscle strength, and physical performance in humans and rodents.</caption><thead><tr><th>Measured parameter</th><th>Humans</th><th>Rodents</th></tr></thead><tbody><tr><td>Muscle Mass</td><td><ul><li>Computed Tomography (CT)</li><li>Magnetic resonance imaging (MRI)</li><li>Dual energy X-ray absorptiometry (DXA)</li><li>Bioelectrical impedance (BIA)</li></ul></td><td><ul><li>Weighing muscle after euthanasia</li><li>Postmortem cross-sectional area</li><li>Methods used in humans</li></ul></td></tr><tr><td>Muscle Strength</td><td><ul><li>Handgrip strength</li><li>Knee flexion/extension (e.g., Cybex)</li></ul></td><td><ul><li>Auto grip strength meter (noninvasive)</li><li>Electrostimulation (very invasive)</li></ul></td></tr><tr><td>Physical Performance</td><td><ul><li>Short Physical Performance Battery (SPPB)</li><li>Gait Speed</li><li>“Timed get-up-and-go” test (TUG)</li><li>Stair climb power test (SCPT)</li></ul></td><td><ul><li>Wire Grip test and Mesh Grip tests</li><li>Beam balance test, tightrope test, and rotarod test</li><li>Maximal aerobic speed test</li><li>Maximal oxygen consumption test</li></ul></td></tr></tbody></table>

<table><caption>Table 2. Positive and negative regulators of G6PDH [adapted from Stanton (2012)].</caption><thead><tr><th>Positive regulators</th><th>Negative regulators</th></tr></thead><tbody><tr><td>PDGF, EGF, VEGF, HGF</td><td>TNF-α</td></tr><tr><td>Insulin</td><td>P38 MAPK</td></tr><tr><td>Benfotiamine (vitamin B1 analog)</td><td>P53</td></tr><tr><td>Vitamin D</td><td>AMPK</td></tr><tr><td>Testosterone, Estrogens</td><td>Aldosterone</td></tr><tr><td>Growth Hormone</td><td>Angiotensin II</td></tr><tr><td>Exercise</td><td>Arachidonic acid</td></tr><tr><td>PI3K, Akt, mTOR, p70S6K</td><td>cAMP</td></tr><tr><td>Nrf2</td><td>cAMP-dependent PKA</td></tr><tr><td>Src</td><td></td></tr><tr><td>TIGAR</td><td></td></tr><tr><td>Hsp27</td><td></td></tr><tr><td>SREBP</td><td></td></tr><tr><td>ATM</td><td></td></tr><tr><td>Phospholipase C</td><td></td></tr><tr><td>cGMP-dependent PKG</td><td></td></tr><tr><td>Ras-GTPase</td><td></td></tr></tbody></table>

Abbreviations: PDGF, platelet-derived growth factor; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; PI-3K, phosphatidylinositol-3-kinase; PKG, protein kinase G; mTOR, mammalian target of rapamycin; TIGAR, TP53-induced glycolysis and apoptosis regulator; Hsp27, heat-shock protein 27; ATM, ataxia telangiectasia mutated; SREBP, sterol-responsive-element-binding protein; PKA, protein kinase A; CREM, cyclic AMP response element modulator; Nrf2,
Special Issue: “Molecular Aspects of Sarcopenia and Frailty”

nuclear-factor-E2-related factor; TNF-α, tumor necrosis factor α; AMPK, adenosine monophosphate-activated protein kinase

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