Skeletal muscle disorders and associated factors that limit exercise performance

The study of skeletal muscle disorders is providing potentially important insights into regulatory mechanisms in human exercise and fatigue and information useful for diagnostic and treatment purposes. This review primarily concerned the general metabolic and physiological factors which set upper limits to performance of various types of exercise in patients with a variety of muscle disorders. From the standpoint of exercise performance, skeletal muscle diseases can be classified into three major groups. One group consists of primary disorders of muscle energy metabolism, including defects in muscle carbohydrate and lipid metabolism, disorders of mitochondrial electron transport, and abnormalities of purine nucleotide metabolism. Exercise performance largely reflects the capacity for ATP resynthesis. Oxidative phosphorylation is the dominant quantitative source of energy for ATP resynthesis under most exercise conditions. Consequently, patients with disordered oxidative metabolism (i.e., patients with defects in the availability or utilization of oxidizable substrate, such as those with phosphorylase or PFK deficiency or those with defects in mitochondrial electron transport) typically demonstrate severely impaired exercise performance. Intolerance to sustained exercise and premature fatigability are salient features of muscle oxidative disorders. Maximal oxygen uptake and maximal a-v O₂ difference are markedly subnormal related to an attenuated muscle oxygen extraction. Muscle weakness and atrophy are less common. Anaerobic muscle performance is dramatically limited in patients with virtually complete defects of glycogenolysis/glycolysis but appears relatively normal in those with electron transport defects. A second major group of disorders includes patients with decreased muscle mass due to muscle necrosis, atrophy, and replacement of muscle by fat and connective tissue. These disorders are exemplified by the various muscular dystrophies (Duchenne’s dystrophy, Becker’s dystrophy, LG dystrophy, FSH dystrophy, and myotonic dystrophy) in which exercise performance is severely impaired due to muscle wasting and weakness in spite of largely normal pathways for muscle ATP resynthesis. In muscular dystrophy patients, the degree to which maximal oxygen uptake and anaerobic muscle performance are impaired appears to be a function of the severity of muscle weakness and atrophy. A third group of disorders includes patients with impaired activation of muscle contraction or relaxation. These disorders may be considered in two subcategories. In the first, impaired activation or relaxation of contractile activity is due to intrinsic muscle dysfunction (e.g., diseases associated with myotonia or periodic paralysis). In the second subcategory, there is impaired muscle activation due to a primary abnormality in the central nervous system, motor nerves, or neuromuscular junction. Diseases of this tvpe (e.g., the motor neuron disease, amyotrophic lateral sclerosis) typically are associated with muscle atrophy secondary to disuse or denervation. Research on exercise performance in patients with impaired muscle activation or relaxation has received little or no systematic attention. The emergence of new clinically applicable noninvasive techniques such as magnetic resonance spectroscopy and imaging is allowing a better understanding of the pathophysiology of many skeletal muscle disorders and is helping to facilitate the assessment of clinical and experimental interventions related to exercise performance.