Review
Muscle type and fiber type specificity in muscle wasting

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Abstract

Muscle wasting occurs in a variety of conditions, including both genetic diseases, such as muscular dystrophies, and acquired disorders, ranging from muscle disuse to cancer cachexia, from heart failure to aging sarcopenia. In most of these conditions, the loss of muscle tissue is not homogeneous, but involves specific muscle groups, for example Duchenne muscular dystrophy affects most body muscles but spares extraocular muscles, and other dystrophies affect selectively proximal or distal limb muscles. In addition, muscle atrophy can affect specific fiber types, involving predominantly slow type 1 or fast type 2 muscle fibers, and is frequently accompanied by a slow-to-fast or fast-to-slow fiber type shift. For example, muscle disuse, such as spinal cord injury, causes type 1 fiber atrophy with a slow-to-fast fiber type shift, whereas cancer cachexia leads to preferential atrophy of type 2 fibers with a fast-to-slow fiber type shift. The identification of the signaling pathways responsible for the differential response of muscles types and fiber types can lead to a better understanding of the pathogenesis of muscle wasting and to the design of therapeutic interventions appropriate for the specific disorders.

This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Introduction

Skeletal muscles are heterogeneous both at the level of whole muscles, motor units and constituent muscle fibers. An obvious diversity pertains to the anatomical position of skeletal muscles within the body, their specific shape and pattern of tendon and bone insertions, all properties which dictate the specific movements that each muscle is able to perform. Physiological properties, such as speed of shortening and resistance to fatigue, also vary among skeletal muscles. Another important aspect of muscle diversity concerns the embryological origin: most body muscles derive from somites, but head muscles derive from the presomitic mesoderm. Distinct genetic programs control the development of extraocular and pharyngeal muscles compared to other body muscles (Sambasivan et al., 2009).

Skeletal muscles also differ with respect to the size of the constituent motor units, namely the number of muscle fibers that each motor neuron innervates, and to the functional properties of the motor units. Three types of motor units, called slow, fast fatigable and fast fatigue resistant motor units, composed by type 1, 2A and 2B fibers, respectively, were initially identified in mammalian skeletal muscle (Burke et al., 1971). A fourth motor unit type, composed by type 2X fibers, was subsequently detected in rat skeletal muscles (Larsson et al., 1991b).

At the single fiber level, it is possible to distinguish four major fiber types, called type 1, 2A, 2X and 2B, based on the presence of specific myosin heavy chain (MyHC) isoforms: MyHC-1/slow, coded by the MYH7 gene, MyHC-2A, coded by MYH2, MyHC-2X, coded by MYH1, and MyHC-2B, coded by MYH4 (Schiaffino and Reggiani, 2011). These fibers also differ in oxidative/glycolytic metabolism, type 1 and 2A fibers being more oxidative and type 2B fibers more glycolytic. These four fiber populations are present in mice, rats and many other mammalian species, however only type 1, 2A and 2X fibers are present in most human muscles (Smerdu et al., 1994). In addition, intermediate hybrid fibers, containing type 1 and 2A, or 2A and 2X, or 2X and 2B MyHCs, are frequent in normal muscles (DeNardi et al., 1993) and become more numerous whenever fiber type shifts take place, thus both in response to exercise (Klitgaard et al., 1990) or electrical stimulation (Maier et al., 1988), or during muscle atrophy induced by denervation (Patterson et al., 2006) and other causes (see below). Muscle wasting also leads to an increased proportion of fibers showing a mismatch between the levels of MyHC isoforms revealed by immunohistochemistry and that of the corresponding mRNAs revealed by in situ hybridization, due to the different turnover of the MyHC proteins and transcripts: these mismatched fibers, indicative of muscle fibers in a transitional state, increase after a bed-rest period in human skeletal muscle (Andersen et al., 1999).

Minor fiber types with more restricted distribution in specific muscles can be identified by the presence of distinct MyHCs. A striking case is that of extraocular muscles (EOMs) which contain, in addition to the four major MyHCs, a unique MyHC-EO isoform, coded by MYH13, and the developmental embryonic and neonatal MyHCs, coded by MYH3 and MYH8, respectively (Sartore et al., 1987, Wieczorek et al., 1985), as well as the recently identified MyHC-slow tonic and MyHC15, coded by the MYH7b and MYH15 genes, respectively (Rossi et al., 2010). EOMs are also characterized by the small size of muscle fibers and the regular coexistence of multiple MyHC isoforms within each fiber.

Finally, in addition to the diversity at the whole muscle, motor unit and muscle fiber level, one can identify an additional layer of heterogeneity at the level of the satellite cells. Satellite cells are stem cells with myogenic potential located under the basal lamina of muscle fibers, which can be activated after muscle injury and are responsible for muscle regeneration (Ciciliot and Schiaffino, 2010), and may also be involved in muscle hypertrophy (Pallafacchina et al., 2012). Satellite cells are heterogeneous with respect to embryological origin (somitic vs non-somitic), postnatal stage (young vs old) and muscle type (fast vs slow) (Biressi and Rando, 2010). Satellite cell heterogeneity may affect the muscle regenerative capacity, for example the masseter muscle regenerates less effectively than limb muscles (Pavlath et al., 1998). The existence of intrinsic differences between satellite cells from fast and slow muscles is further suggested by the finding that electrical stimulation of regenerating slow soleus and fast extensor digitorum longus (EDL) muscles with the same slow stimulus pattern in the absence of innervation leads to widespread slow MyHC expression in regenerated soleus but only limited expression of slow MyHC in regenerated EDL (Kalhovde et al., 2005).

Muscle diversity, fiber type diversity and satellite cell diversity may also affect the susceptibility of different muscles and fiber types to disease, including their response to muscle wasting. In this review, we will consider congenital and acquired muscle diseases leading to muscle wasting from the point of view of muscle diversity. We will discuss two related though not necessarily associated changes: (i) muscle wasting conditions involving predominantly atrophy of slow type 1 or fast type 2 muscle fibers and (ii) muscle wasting conditions accompanied by slow-to-fast or fast-to-slow fiber type shift.

Section snippets

Genetic myopathies leading to muscle wasting

Muscular dystrophies affect skeletal muscles differentially (Fig. 1). For example, Duchenne muscular dystrophy (DMD) affects most body muscles, but spares head muscles, including EOMs, which are affected in oculopharyngeal muscular dystrophy. Limb-girdle muscular dystrophy affects proximal, but not distal muscles of the limbs, whereas the opposite is true for the distal forms of muscular dystrophy. Wide variations among muscle types are seen in facioscapulohumeral muscular dystrophy (FSHD):

Acquired muscle wasting syndromes

Muscle wasting occurs in a variety of conditions ranging from muscle disuse to cancer cachexia, from heart failure to aging sarcopenia. In most of these conditions muscle atrophy occurs preferentially in certain fiber types and/or is accompanied by shifts in fiber type profile. Muscle disuse involving loss of neural influence and mechanical loading causes a slow-to-fast shift in fiber type and MyHC isoform profile, usually but not always accompanied by preferential atrophy of type 1 slow fibers

Mechanisms underlying muscle type-specific susceptibility to muscle wasting

Muscle wasting may be the result of a decrease in protein synthesis and an increase in muscle protein breakdown, which in turn reflects the activation of two major pathways, the proteasomal and the autophagic-lysosomal systems (Schiaffino et al., 2013). Both pathways are controlled by the transcription factor FoxO3 (Mammucari et al., 2007, Sandri et al., 2004), which is negatively regulated by Akt, thus fiber type specificity in muscle wasting might be due to differences in the regulation of

Conclusions

The mechanisms responsible for the differential susceptibility of the various muscle types and fiber types to muscle wasting are difficult to dissect, given the variety of conditions and diseases, some of which cause rapid loss of muscle mass, e.g. fasting or disuse, while others develop over months or years, e.g. aging sarcopenia. In addition, the study of many of these conditions is complicated by the multiplicity of local and systemic changes, for example during aging there are changes in

Acknowledgments

Original work reported here has been supported by the EC FP7 Project MYOAGE (grant no. 223576 to SS) and by a grant from the Agenzia Spaziale Italiana (ASI to SS).

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    This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

    1

    These authors contributed equally to this work.

    2

    Present address: Department of Molecular, Cellular and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO, USA.

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