Muscle fibre types: their role in health, disease and as therapeutic targets

Introduction Accounting for approximately half of the body weight, the skeletal muscle is the largest organ in the human body. The functional significance of the muscle is seen in the two-fold purpose it serves–as a source of force production for locomotion and as a major regulatory organ for glucose and fatty acid metabolism. This short review will focus on muscle fibre types, starting with a brief historical overview of fibre types, their physiological and metabolic significance, how fibre type plasticity affects both contractile and metabolic properties of muscle and how these properties relate to human diseases known to exhibit muscle fibre type (slowtwitch vs. fast-twitch) disproportion. Also, based on recent animal model experiments, this paper discusses the efficacy of using fibre type manipulation for therapeutic purposes. Conclusion Because of its adaptability to external stimuli and easy accessibility, skeletal muscle remodeling could be a viable therapeutic approach for various diseases manifesting fibre type shifts. Reduced ratios of slowoxidative muscle are significantly associated with obesity and type 2 diabetes. Recent information obtained from animal model studies for metabolic syndrome and muscle atrophy present multiple candidate genes and signaling pathways for use as therapeutic targets. As more detailed molecular mechanisms of fibre type specification and plasticity are revealed, manipulating physiological properties of skeletal muscle holds a promise for treatment of obesityinduced clinical conditions as well as muscle atrophy. Introduction Heterogeneity is the foundation for the functional plasticity of the skeletal muscle. Muscle fibres contain a bundle of myofibrils, which consist of tandem repeats of sarcomeres, the contractile unit of skeletal muscle (Figure 1). The defining physiological properties of each muscle fibre–its contraction speed (slow/fast) and metabolic capacity (oxidative/glycolytic)–are a functional culmination of the coordinated expression of numerous sarcomeric contractile protein isoforms and metabolic enzymes. Therefore, the functionality of each muscle fibre is a summation of these properties and the resultant combination is termed ‘fibre type’. Visual recognition of muscle fibre type–red versus white–has been reported for centuries1; however, only in the past 50 years has the extent of heterogeneity of muscle been fully appreciated. As an organ, human muscle is a checker board of these heterogeneous fibre types, allowing remarkable adaptation to various tasks requiring different degrees of intensity and duration. Although muscle fibre type specification occurs during development2, fibre type is not static in adult life. In addition to the activity-induced functional plasticity seen in normal adult muscle, disuse of muscle and diseaseinduced pathologies can selectively influence muscle fibre types, inducing different responses between fibre types. One common response associated with pathologic conditions is the predominance of one fibre type over the others. This phenomenon has been recognized as a significant clinical feature for human neuromuscular diseases over 40 years3. In spite of this decades old observation, three major unknowns still remain for any given disease: (1) what determines the differential responses between muscle fibre types, (2) whether predominance of one fibre type is causal or secondary to the pathological condition and (3) whether manipulating muscle fibre type can improve pathological * Corresponding author Email: nhagiwara@ucdavis.edu Department of Internal Medicine, Division of Cardiovascular Medicine, University of California, Davis, California, USA Figure 1: Skeletal muscle fibre.