ORIGINAL ARTICLE Andrei B. Borisov Æ Eduard I. Dedkov Bruce M. Carlson Abortive myogenesis in denervated skeletal muscle: differentiative properties of satellite cells, their migration, and block of terminal differentiation Accepted: 17 September 2004 / Published online: 11 March 2005 Ó Springer-Verlag 2005 Abstract Little is known about the biological properties of myogenic satellite cells during postdenervation muscle atrophy. The present study investigated the differentia- tive capacity of satellite cells and their involvement in the compensatory regenerative process in long-term denervated rat muscle. Electron microscopy and immu- nocytochemical labeling of muscle tissue 1–18 months following denervation demonstrated that despite acti- vation of satellite cells, myogenesis in denervated muscle is abortive and does not lead to the formation of normal muscle fibers. Small sizes, poor development of the contractile system in newly formed denervated myotu- bes, and the absence of satellite cells on the surface indicate that their differentiation typically does not progress to terminal stages. Many immature myotubes degenerate, and others survive but are embedded in a collagen lattice near their parent fibers. Interestingly, newly formed myotubes located on the surface of parent muscle fibers beneath the basal lamina typically did not contain developed myofibrils. This suggests that the contacts of daughter and parent muscle fibers block myofibrillogenesis. Assembly of sarcomeres in most cases occurs following complete spatial separation of daughter and parent muscle fibers. Another manifesta- tion of the involvement of myogenic precursors in abortive myogenesis is the formation of clusters of underdeveloped branching myotubes surrounded by a common basal lamina. We found that myoblasts can also fuse directly with differentiated muscle fibers. The presence of satellite cells near the openings in the basal lamina and in the interstitial space indicates that myo- genic precursors can migrate through the basal lamina and form myotubes at a distance from parent fibers. Our data may explain why long-term denervated skeletal muscle has a poor capacity for regeneration and func- tional restoration. Keywords Skeletal muscle Æ Denervation Æ Myogenesis Æ Satellite cells Introduction Innervation is an important trophic and regulatory factor controlling terminal differentiation, stability of the differentiated phenotype, and functional activity of skeletal muscle cells. The loss of innervation results in progressive atrophy of muscle tissue and rapid impair- ment of its functional capacity. Structural changes and the dynamics of the atrophic process in denervated skeletal muscle at microscopic and ultrastructural levels have been described in a number of publications (see Schmalbruch and Lewis 1994; Lu et al. 1997; Borisov and Carlson 2000; Borisov et al. 2001). More than 40 years of electron microscopic and histological studies have provided detailed descriptions of fine structural characteristics of denervated muscle. At the same time, little is known regarding the cellular mechanisms that underlie postdenervation muscle atrophy. Understand- ing of the molecular pathways of myogenesis and the recent development of probes specific for different stages of this process opens new horizons for causal analysis of the cellular basis and pathogenesis of postdenervation muscle atrophy. One of the key issues that are directly related to the mechanisms of this process is the eluci- dation of the differentiative properties and activity of myogenic satellite cells. This reserve of myoblasts A. B. Borisov (&) Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan, Room 8200, MSRB III, Ann Arbor, MI 48109, USA E-mail: aborisov@umich.edu Tel.: +1-734-9368663 Fax: +1-734-6151386 E. I. Dedkov Æ B. M. Carlson Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-0616, USA B. M. Carlson Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109-0616, USA Anat Embryol (2005) 209: 269–279 DOI 10.1007/s00429-004-0429-7