**Author details**

nated proteins, and sarcomere disorganization [99]. In addition, the central role of the autoph‐ agy-lysosome system in muscle homeostasis is highlighted by lysosomal storage diseases (Pompe disease, Danon disease, and X-linked myopathy). These diseases are a group of debilitating muscle disorders characterized by alterations in lysosomal proteins and autopha‐ gosome buildup [124]. Intriguingly, the accumulation of autophagic vacuoles inside myofibers

**Figure 4.** The comparison of an autophagy-dependent system between young and sarcopenic muscle. In contrast to young muscle, sarcopenic muscle exhibits abundant p62/SQSTM1 proteins with no activation of LC3, showing appa‐

*p62/SQSTM1 LC3*

*degenerative protein*

Sarcopenic muscle

Various muscular dystrophies also exhibit the apparent defect of autophagy-dependent signaling. The first evidence of impaired autophagy in these models was provided by studies in mice and patients with mutations in collagen VI [125]. Mutations that inactivate Jumpy, a phosphatase that counteracts the activation of VPS34 for autophagosome formation and reduces autophagy, are associated with centronuclear myopathy [126]. De Palma et al. [127] have described a decreased expression of autophagic regulator proteins (i.e., LC3 II, Atg12, GABARAPL-1, Bnip3) in dystrophin-deficient mdx mice and DMD patients. In addition, starvation and treatment with chloroquine, potent inducers of autophagy, did not activate autophagy-dependent signaling in both tibialis anterior and diaphragm muscles of mdx mice [127]. Furthermore, mdx mice and DMD patients exhibited an unnecessary accumulation of p62/SQSTM1 protein, which was lost after prolonged autophagy induction by a low-protein diet [127]. A similar block in autophagy progression was described in lamin A/C null mice [128]. LGMD2A muscles showed up-regulation of p62/SQSTM1 (2.1-fold) and Bnip3 (3-fold) mRNA and slightly increased LC3-II/LC3-I protein ratio and p62/SQSTM1 [87]. Conversely, laminin-mutated (*dy/dy*) animals displayed excessive levels of autophagy, which is equally detrimental [129]. These findings suggest that the defect of autophagy signaling has a central

is recognized in all of these myopathies because of defects in their clearance.

Young muscle

158 Muscle Cell and Tissue

rent autophagy defects, which cannot destroy the degenerative proteins.

role in the degenerative symptoms in various types of muscular dystrophy.

Kunihiro Sakuma1\* and Akihiko Yamaguchi2

\*Address all correspondence to: ksakuma@las.tut.ac.jp

1 Research Center for Physical Fitness, Sports and Health, Toyohashi University of Technol‐ ogy, 1-1 Hibarigaoka, Tenpaku-cho, Toyohashi, Japan

2 Department of Physical Therapy, Health Sciences University of Hokkaido, Kanazawa, Ishi‐ kari-Tobetsu, Hokkaido, Japan
