Muscle type and fiber type specificity in muscle wasting

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May 21, 2013 - whereas cancer cachexia leads to preferential atrophy of type 2 fibers with a fast-to-slow fiber type shift. The identification of the signaling ...
The International Journal of Biochemistry & Cell Biology 45 (2013) 2191–2199

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Muscle type and fiber type specificity in muscle wasting夽 Stefano Ciciliot a,1 , Alberto C. Rossi a,1,2 , Kenneth A. Dyar a , Bert Blaauw a,b , Stefano Schiaffino a,c,∗ a b c

Venetian Institute of Molecular Medicine (VIMM), Padova, Italy Department of Biomedical Sciences, University of Padova, Padova, Italy Consiglio Nazionale delle Ricerche (CNR), Institute of Neuroscience, Padova, Italy

a r t i c l e

i n f o

Article history: Available online 21 May 2013 Keywords: Muscle atrophy Muscle fiber types Cachexia Muscular dystrophies Muscle disuse Sarcopenia

a b s t r a c t 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. © 2013 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2191 Genetic myopathies leading to muscle wasting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192 Acquired muscle wasting syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2193 Mechanisms underlying muscle type-specific susceptibility to muscle wasting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2195 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2197 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2197 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2197

1. 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

夽 This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. ∗ Corresponding author at: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy. Tel.: +39 049 7923 232; fax: +39 049 7923 250. E-mail addresses: stefano.schiaffi[email protected], stefano.schiaffi[email protected] (S. Schiaffino). URL: http://www.vimm.it (S. Schiaffino). 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. 1357-2725/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.biocel.2013.05.016

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,

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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

Fig. 1. Distribution of predominant muscle wasting in different types of muscular dystrophies: (A) Duchenne, (B) Emery–Dreifuss, (C) limb-girdle, (D) facioscapulohumeral, (E) distal, and (F) oculopharyngeal. Affected areas are shaded. Modified from Emery (2002).

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. 2. 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. Limbgirdle 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): facial muscles but not EOMs are affected, and the muscles of the anterior compartment of the leg, such as the tibialis anterior, are more affected compared to the muscles of the posterior compartment, such as the gastrocnemius (Table 1). Wide differences are also observed in animal models of muscular dystrophies: for example, the dystrophin-deficient mdx mouse, a model of human DMD, shows a mild pathological phenotype in most skeletal muscles, except for the diaphragm, which is severely affected. The factors underlying these differences are completely unknown. The sparing of EOMs in the dystrophin-deficient mdx

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Table 1 Variation in the degree of pathological changes in muscles from patients with facioscapulohumeral muscular dystrophy (FSHD). Muscle type

Dystrophic changesa

Vastus lateralis Tibialis anterior Soleus Gastrocnemius Diaphragm Biceps brachii Triceps brachii Pectoralis Masseter Trapezius

+++ ++++ + + − ++ ++ +++ − +++++

a Range of dystrophic changes taking into consideration fiber size variation, internal nuclei, fibrosis, necrosis, regeneration, lysosomal activity: −, normal; + minimal changes; +++++, severe dystrophic changes. Modified from Gabellini et al. (2006).

mouse, a model of DMD, is especially striking (Karpati et al., 1988) and has been the object of several investigations. Interestingly, while the EOMs proper, namely the six oculorotatory muscles (four recti and two obliqui), are spared, two other eye muscles, the retractor bulbi and the levator palpebrae superioris, which are more similar to other body muscles in terms of fiber size and fiber type composition, exhibit a level of pathology intermediate between EOMs and limb muscles (Porter et al., 1998). The upregulation of the dystrophin analog utrophin has been suggested to be a major factor in the rescue of eye muscles in this muscular dystrophy, based on the finding that (i) utrophin levels are higher in EOM than limb muscles and are further increased in EOMs of mdx mice and (ii) mice deficient in both utrophin and dystrophin exhibit severe dystrophic changes also in EOMs (Porter et al., 1998). An alternative possibility is that EOMs have increased regenerative capacity compared to body muscles, due to the greater number and distinct properties of EOM satellite cells (Kallestad et al., 2011; Pacheco-Pinedo et al., 2009). EOMs are also spared in neurogenic muscle wasting diseases, such as amyotrophic lateral sclerosis, however this reflects a difference in motoneuron susceptibility to disease, spinal motoneurons undergoing progressive degeneration and death, whereas motoneurons of the oculomotor system are left intact. Fast muscle fibers are preferentially affected in DMD (Webster et al., 1988), and muscle fibers expressing MyHC-2X transcripts disappear early in DMD muscles (Pedemonte et al., 1999). Type 2 and especially type 2B fibers are preferentially involved in a mouse model of FSHD, showing a much larger force deficit than type 1 fibers (D’Antona et al., 2007). Accordingly, a marked reduction in active force was reported in type 2 but not type 1 skinned fibers isolated from muscle biopsies of FSHD patients (Lassche et al., 2013). A fiber type size disproportion, with type 1 muscle fibers being much smaller than type 2 fibers, is frequently seen in congenital myopathies due to different genetic mutations. In some patients, the difference in size is especially marked and, in the absence of other morphological alterations suggesting a different diagnosis, the term “congenital fiber type disproportion” (CFTD) has been introduced to define this syndrome (Clarke, 2011). CFTD is caused by mutations in the ACTA1 gene, coding for ␣-skeletal actin, or TPM3, coding for ␥-tropomyosin, or RYR1, coding for ryanodine receptor type 1 (Fig. 2A). The muscle wasting observed in these conditions is actually the result of impaired developmental growth of type 1 fibers, which is often accompanied by hypertrophy of type 2 fibers. Whereas ␥-tropomyosin is predominantly expressed in slow fiber types, the ACTA1 and RYR1 genes are expressed in both fast and slow fibers, therefore it is difficult to explain the dramatic difference in size between type 1 and 2 fibers in these patients. It should be stressed that mutations of these genes cause CFTD only in some families, while they are more commonly associated

Fig. 2. Genetic myopathies affecting selectively different muscle fiber types. (A) Atrophy of type 1 fibers (dark) contrasting with hypertrophy of type 2 fibers (pale) in a patient with congenital fiber type disproportion due to mutation of RYR1, coding for ryanodine receptor 1. Section stained for myosin ATPase after preincubation at pH 4.3. Modified from Clarke (2011). Scale bar: 25 ␮m. (B) Atrophy of type 2A fibers in a patient with mutation of MYH2, coding for MyHC-2A, revealed by myosin immunostaining. Modified from Oldfors (2007). Scale bar: 50 ␮m.

with other diseases, ACTA1 mutations with nemaline myopathy and RYR1 mutations with malignant hyperthermia and central core disease. Selective atrophy of specific fiber types is also observed in myosinopathies caused by mutations of MYH genes, including MYH2, coding for MyHC-2A, and MYH7, coding for slow MyHC-1 (Tajsharghi and Oldfors, 2013). The clinical and pathological phenotype of myosinopathies is highly variable, also in relation with the specific mutations, but in a number of cases the disease is characterized by reduced size of specific fiber types, for example patients with MYH2 mutations may have few and small type 2A muscle fibers (Fig. 2B). 3. 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 (Table 2). This may occur as a result of denervation or limb immobilization due to casting (Herbison et al., 1979), spinal cord injury (Grimby et al., 1976), bed

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S. Ciciliot et al. / The International Journal of Biochemistry & Cell Biology 45 (2013) 2191–2199 Table 2 Muscle wasting conditions involving predominantly type 1 or type 2 muscle fiber atrophy with slow-to-fast or fast-to-slow fiber type shift, respectively. Mechanism

Fiber type shift Slow-to-fast

Loss of neural influence and mechanical loading

Fast-to-slow

Denervation Spinal cord injury Limb immobilizationa Hindlimb suspension Bed rest Microgravity (space flights)

Malnutrition and inflammation

Fasting Glucocorticoid administration Type 1 diabetes Sepsis Cancer cachexia AIDS cachexia

Multiple factors

Aging

Multiple factors

Heart failure (limb muscles) COPD (limb muscles)

Heart failure (diaphragm) COPD (diaphragm)

a

Limb immobilization in a shortened position leads to muscle atrophy with a slow-to-fast fiber type shift, however limb immobilization in a lengthened position leads to hypertrophy with a fast-to-slow fiber type shift (Loughna et al., 1990).

Fig. 3. Slow-to-fast fiber type shift induced by inactivity in human skeletal muscle. Normal human vastus lateralis muscle (left panels) compared with muscle from a paraplegic individual, about one year after spinal cord injury (right panels). Serial sections of muscle biopsies were stained with antibodies specific for fast type 2 MyHCs (upper panels) and slow type 1 MyHCs (lower panels). Note the complete slow-to-fast fiber type shift induced by spinal cord injury contrasting with the typical mixed fiber type profile of normal human muscle. Also note the marked atrophy of paralyzed muscle fibers. Modified from Schiaffino (2010). Scale bar: 100 ␮m.

rest (Grimby et al., 1976) and microgravity (Ohira et al., 1992). A similar slow-to-fast shift, involving MyHC, troponin T and troponin I isoforms, is found after hindlimb suspension, an animal model of microgravity (Campione et al., 1993). In humans, spinal cord injury often leads to the complete disappearance of type 1 fibers (Fig. 3). However, it should be stressed that the same fiber type may respond differently to denervation according to muscle type. For example, type 1 fibers of the rat slow soleus muscle undergo dramatic atrophy after denervation, whereas type 1 fibers in the fast EDL muscle maintain essentially the same size during the first two weeks after sciatic nerve section (Fig. 4). A similar difference

Fig. 4. Differential response to denervation of type 1 fibers in rat slow soleus and fast extensor digitorum longus (EDL) muscle. Muscles analyzed at 7 days (A) and 14 days (B) after sciatic nerve section. Transverse sections were stained with antibodies specific for MyHC-1/slow (red) and counterstained for laminin (green) to better visualize the fiber profile. Note the dramatic atrophy of type 1 fibers in denervated soleus, whereas the type 1 fibers in EDL are essentially unchanged in size after nerve section. In contrast, the unstained EDL type 2 fibers, which are normally larger than type 1 fibers, undergo marked atrophy in denervated EDL and most of them become smaller than type 1 fibers by 14 days. Scale bars: 50 ␮m. (For interpretation of the references to color in this artwork, the reader is referred to the web version of the article.)

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is observed in type 2A fibers, which undergo marked atrophy in soleus, but only slight atrophy in EDL. In the rat diaphragm muscle, denervation was likewise reported to cause atrophy of type 2X and 2B fibers, no change in type 2A and hypertrophy of type 1 fibers (Aravamudan et al., 2006). An opposite response, namely a fast-to-slow shift with preferential atrophy of fast glycolytic muscle fibers, is induced by fasting (Li and Goldberg, 1976), glucocorticoid administration (Goldberg and Goodman, 1969), streptozotocin-induced diabetes (Armstrong et al., 1975) or sepsis (Tiao et al., 1997) (Table 2). Similar changes are seen in cancer cachexia: selective atrophy of type 2 fibers was described in muscle biopsies from human cancer patients (Mendell and Engel, 1971) and in mouse models of cancer cachexia (Acharyya et al., 2005). The homozygous HIV-1 transgenic mouse line Tg26, which reproduces the wasting syndrome of AIDS patients, shows atrophy of type 2X and 2B fibers in the fast EDL and gastrocnemius muscles, but not of type 1 and 2A fibers in the slow soleus muscle (Serrano et al., 2008). Nutritional deprivation and release of proinflammatory cytokines, such as TNF␣, have been implicated in these conditions. A fast-to-slow fiber type shift is also seen during aging, when muscle atrophy is especially evident in type 2B fibers and is accompanied by a type 2B to 2X MyHC switching in rat tibialis anterior (Larsson et al., 1993) and by a type 2A to type 1 fiber type switching in plantaris muscle (Holloszy et al., 1991). In human skeletal muscle, type 2 fibers are atrophic in old individuals, while the size of type 1 fibers is much less affected by age (Lexell, 1995). Age-dependent changes in motor unit composition have also been described. Whereas in young rats all motor units had a homogeneous fiber type composition, in old rats motor units predominantly composed of type 2X fibers frequently contained also type 2A or type 2B fibers as well as hybrid fibers (Larsson et al., 1991a). It is likely that these changes reflect an altered neuromuscular control. Indeed, synaptic dysfunction at the neuromuscular junctions (NMJs) is emerging as an important factor in the pathogenesis of aging sarcopenia. Age-related changes of NMJs include fragmentation of the postsynaptic membrane, defined by junctional acetylcholine receptors (AChRs), and incomplete occupation of the postsynaptic apparatus by nerve terminals. These changes are especially prominent in most limb and trunk muscles, whereas EOMs are strikingly spared (Fig. 5) (Valdez et al., 2012). EOMs are likewise resistant to NMJ disruption in amyotrophic lateral sclerosis both in humans and in mouse models. Chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) cause a slow-to-fast fiber type shift with a decrease in slow MyHC-1 and an increase in fast MyHC-2X protein levels in limb muscles (Satta et al., 1997; Sullivan et al., 1997) (Table 2 and Fig. 6). The decreased proportion of oxidative, fatigue-resistant type 1 fibers is probably responsible for the exercise intolerance observed in patients with CHF and COPD. The similarity of this shift to that induced by inactivity suggests that reduced physical activity, also referred to as deconditioning, is involved in these changes. However, additional factors, including increased levels of inflammatory cytokines, malnutrition, hypoxia and oxidative stress may contribute to the fiber type shift (Remels et al., 2012). Interestingly, a change in the opposite direction, i.e. a fast-to-slow fiber type and myosin shift, is found in respiratory muscles, like the diaphragm, both in COPD (Levine et al., 1997; Mercadier et al., 1998) and CHF (Tikunov et al., 1997) (Table 2 and Fig. 6). This can be explained by the fact that these patients hyperventilate both during rest and exercise, therefore the respiratory muscles undergo a constant moderate-intensity exercise similar to that induced by endurance exercise in limb muscles of normal individuals. However, expecially in severe COPD, both type 1 and 2 fibers in the diaphragm show a decreased fiber size, presumably due to

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Fig. 5. Muscle specificity in age-related alterations of neuromuscular junctions (NMJs). EDL muscles (A) and extraocular muscles (EOM) (B) from 4-month-old (young) and 24-month-old (old) transgenic mice expressing YFP in axons (green) were stained with ␣-bungarotoxin to label acetylcholine receptors (AchRs) in the postsynaptic membrane (red). Note that while axons and AChR aggregates are precisely aligned in muscles from young mice, large areas of the postsynaptic apparatus are not occupied by axons in EDL from old mice. In contrast, these alterations are absent in EOMs. Scale bars: 10 ␮m. (For interpretation of the references to color in this artwork, the reader is referred to the web version of the article.) From Valdez et al. (2012).

concomitant increase in inflammatory cytokines and oxidative stress, as well as corticosteroid therapy (Remels et al., 2012). 4. 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 FoxO3 activity. Other pathways controlling muscle size are the myostatin-Smad2/3 pathway and the transcription factor NF-␬B, both of which may also display fiber type specificity. The transcriptional co-activator PGC-1␣, which is more abundant in slow oxidative than in fast glycolytic muscle fibers, is involved in FoxO3 regulation. FoxO3 promotes the transcription of the ubiquitin ligases Atrogin1/MAFbx and MuRF1 (Sandri et al., 2004; Stitt et al., 2004), which is induced before the onset of muscle atrophy and is necessary for the atrophy process (Bodine et al., 2001; Gomes et al., 2001). PGC-1␣ was found to prevent FoxO3 binding to the Atrogin1/MAFbx promoter and to inhibit Atrogin1/MAFbx transcription (Sandri et al., 2006). Importantly,

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Fig. 6. Differential changes in slow and fast MyHCs in limb muscles (vastus lateralis) and diaphragm from normal individuals (C) and patients with chronic obstructive pulmonary disease (COPD) or heart failure (HF). MyHCs in muscle biopsies were analyzed by SDS-PAGE. The relative levels of slow MyHC-1 and fast MyHC-2X are expressed as % of total MyHCs (MyHC-2A changes were generally not significant). In COPD, MyHC-1 was decreased in vastus but increased in diaphragm, whereas MyHC2X was increased in vastus but decreased in diaphragm. Similar changes were seen in HF, except that MyHC-1 was unchanged in diaphragm. All differences between each experimental group and the corresponding control were statistically significant, except for the difference in MyHC-1 between COPD and control in vastus lateralis muscle. Graphs designed from original data reported for COPD vastus lateralis (Satta et al., 1997), COPD diaphragm (Levine et al., 1997), HF vastus (Satta et al., 1997) and HF diaphragm (Tikunov et al., 1997).

PGC-1␣ overexpression inhibits the loss of muscle mass induced by starvation and FoxO3 overexpression. These findings can explain why type 2B fibers, which contain lower levels of PGC-1␣, are more susceptible to fasting- and glucocortocoid-induced muscle atrophy, while exercise, which is known to induce PGC-1␣ expression, has a protective effect against muscle atrophy (Falduto et al., 1990). On the other hand, denervation causes a rapid loss of PGC-1␣, thus type 1 fibers become sensitive to muscle wasting after denervation. PGC-1␤ has similar effects, as PGC-1␤ overexpression inhibits protein breakdown by reducing both proteasomal and lysosomal degradation and thus prevents muscle fiber atrophy (Brault et al., 2010). Increased muscle PGC-1␣ expression was also reported to protect against sarcopenia during aging (Wenz et al., 2009) and in a mouse model of heart failure (Geng et al., 2011). While the ubiquitin–proteasomal system has a major role in muscle wasting, the contribution of the autophagic-lysosomal systems is apparently less important (Mitch and Goldberg, 1996). Autophagy is induced by starvation in fast EDL and plantaris but not in slow soleus muscle, as determined by autophagosome visualization with GFP-LC3 (Mizushima et al., 2004; Ogata et al., 2010) (Fig. 7A). However, it is unlikely that this explains the greater susceptibility of fast muscles to starvation-dependent muscle atrophy, because inhibition of autophagy, induced by muscle-specific knockout of the autophagy gene Atg7, does not prevent, but on the contrary exacerbates muscle loss (Masiero et al., 2009). Although the transcripts of different autophagy genes are upregulated by denervation (Sandri et al., 2004), autophagosome formation is not induced by denervation in fast and slow muscles (Quy et al., 2013) (Fig. 7B). Another pathway controlling autophagy in a fiber typespecific manner has been recently identified: Fyn, a member of the Src family of nonreceptor tyrosine kinases, has an inhibitory effect on autophagosome formation via a STAT3-Vps34 pathway, and during starvation Fyn kinase activity significantly decreases only in fast glycolytic fibers, leading to increased autophagy (Yamada et al., 2012). In addition, transgenic mice overexpressing Fyn in skeletal muscle display a muscle atrophy phenotype typical of starvation and aging sarcopenia, with selective loss of fast glycolytic but not slow oxidative muscle fibers. Muscle wasting induced by sepsis, cachexia, starvation and acute diabetes is characterized by a fast-to-slow fiber type shift similar to that induced by glucocorticoids. Indeed, glucocorticoids are essential for muscle atrophy in these conditions, as shown by the finding that adrenalectomy or muscle-specific knockout of

Fig. 7. Differential effect of starvation and denervation on autophagosome formation in fast and slow muscles. (A) Autophagosomes are induced by starvation (24 h) in fast EDL but not in slow soleus (SOL) muscle. Modified from Mizushima et al. (2004). (B) Autophagosomes are induced by starvation (48 h) in innervated (Inn) but not in denervated (Den) gastrocnemius muscle. Modified from Quy et al. (2013). In both (A) and (B) autophagosomes are visualized as fluorescent dots (puncta) in transverse sections of skeletal muscles from transgenic mice expressing GFP-LC3. Scale bars: 20 ␮m.

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the glucocorticoid receptor inhibit muscle wasting in these states (Hasselgren, 1999; Hu et al., 2009). Glucocorticoids appear to act both by activating a transcriptional program of muscle atrophy, including activation of the ubiquitin ligase MuRF1 (Waddell et al., 2008), and by interfering directly with insulin signaling, leading to repression of Akt activation and consequent upregulation of FoxO transcription factors (Hu et al., 2009). Increased levels of inflammatory cytokines, such as tumor necrosis factor ␣ (TNF␣), may also contribute to the selective atrophy of fast muscle fibers in sepsis and cancer cachexia. TNF␣ activates the NF-␬B pathway, leading to the upregulation the muscle-specific ubiquitin ligase MuRF1 (Cai et al., 2004), which ubiquitylates myosin and other thick filament proteins (Cohen et al., 2009), as well as actin and other thin filament proteins (Kedar et al., 2004; Polge et al., 2011). Transgenic mice with muscle-specific constitutive activation of the NF-␬B pathway display atrophy of fast but not slow skeletal muscles (Cai et al., 2004). Myostatin, a negative regulator of muscle growth, has been implicated in skeletal muscle wasting induced by COPD (Remels et al., 2012) and CHF (Heineke et al., 2010). Myostatin is upregulated in cardiac muscle and is increased in serum after induction of heart failure. In a mouse model of heart failure, muscle wasting was more pronounced in slow soleus than in fast quadriceps and gastrocnemius muscles and was completely prevented by cardiac-specific deletion of Mstn, the myostatin gene (Heineke et al., 2010). In addition, cardiac-specific overexpression of Mstn, which markedly increases circulating levels of myostatin, causes a reduction in weight more pronounced in soleus than in fast muscles. Myostatin is also secreted by cancer cells and might thus contribute to skeletal muscle wasting during cancer cachexia (Lokireddy et al., 2012). Myostatin null mice show a decrease in oxidative type 2A and 2X fibers and an increase in glycolytic 2B fibers (Amthor et al., 2007). However, this change reflects an effect of myostatin loss on fiber type diversification during development, because inhibition of myostatin with a specific antibody in adult mice did not cause a transformation to the fast glycolytic phenotype (Girgenrath et al., 2005). In both CHF and COPD, hypoxia has also been implicated as a factor contributing to muscle wasting. Interestingly, hypoxia is known to induce the activation of the transcription factor HIF-1␣, which, when overexpressed, can induce a slow-to-fast fiber type switch (Lunde et al., 2011).

5. 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 food intake, activity pattern, hormonal levels, etc., and multiple factors may likewise be responsible for muscle atrophy induced by CHF and COPD. It has been suggested that different types of muscle atrophy share a common transcriptional program that is activated both in catabolic disorders, such as fasting and cancer cachexia (Lecker et al., 2004), and in disuse atrophy, such as that induced by denervation or spinal cord isolation (Sacheck et al., 2007). However, many recent studies point to the existence of significant differences between the various conditions. For example, autophagy is strongly activated in skeletal muscles during starvation but not after denervation (Quy et al., 2013). In addition, the markedly different response of muscle fiber types in various atrophy models points to tissue-specific mechanisms that variably modulate the activation of muscle atrophy

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