Table 1:

Etiologies of Limb Muscle Atrophy, Weakness, and Susceptibility to Fatigue

	Mechanisms Involved
Factors leading to muscle atrophy and weakness
Disuse	Associated with weakness, atrophy, changes in fiber type distribution, and metabolic alterations (303–306, 310)
Inflammation	Triggering of the muscle proteolysis cascade (102, 116, 322, 325)
Oxidative stress	Triggering of the muscle proteolysis cascade (336, 339, 340)
	Associated with reduced muscle endurance (222, 227, 229)
	Protein carbonylation possibly involved in exercise intolerance and weakness (201)
Hypoxemia	Decreased muscle protein synthesis
	Activation of muscle degradation through hypoxia-inducible factor/von Hippel–Lindau signaling cascade (347–350)
Hypercapnia	Intracellular acidosis/alterations in contractile protein synthesis/degradation (105, 362)
Low levels of anabolic hormones and growth factors	Associated with reduced muscle protein synthesis (371, 372)
Impaired energy balance	Associated with reduced muscle protein synthesis (381, 383)
Corticosteroids	Reduced muscle protein synthesis and enhanced proteolysis through increased myostatin levels and reduced insulin-like growth factor-1 levels (385)
Vitamin D deficiency	Associated with muscle weakness, type II atrophy impaired calcium metabolism (392, 400, 405)
Factors leading to muscle susceptibility to fatigue
Central fatigue—afferent feedback from limb muscles	Reduced motor output to the contracting muscles (295)
Reduced O2 delivery (impaired cardiac output, blood flow competition between the respiratory and limb muscle, reduced capillarity)	Changes in muscle metabolism in favor of glycolysis; accumulation of muscle metabolites associated with muscle fatigue
Muscle metabolic alteration (reduced oxidative enzyme activity, reduced mitochondrial function)	Preferential use of glycolysis and accumulation of muscle metabolites associated with muscle fatigue (179, 180, 190, 199, 443)