Musculoskeletal System

Skeletal Muscle - Degeneration

Narrative

Comment:

Degenerated muscle can grossly appear either pale or dark. Histologically, degenerating myofibers can exhibit a variety of microscopic changes, including cell swelling, hypereosinophilia, vacuolation, loss of striation, fragmentation, and rupture of fibers (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, and Figure 7). Ruptured fibers can often be identified by the presence of "retraction caps," which are concavities at the free ends of the ruptured fibers. Macrophages are often noted in close association with degenerating myofibers, as they play an important role in phagocytizing associated debris (Figure 4). Due to the long length of muscle fibers, degeneration often only affects a segment or several segments of the fiber, as opposed to the entire myofiber. Regions of degeneration can be variably accompanied by additional myopathic changes, such as necrosis, atrophy, compensatory hypertrophy, regeneration, and fibrosis (Figure 5).

Degeneration is a common sequela of myofiber injury, regardless of the cause. Common causes include chemical irritants/myotoxins, abnormal metabolism, trauma, and infection. As in other tissues, degeneration can be reversible; however, if the injurious stimulus persists, a "point of no return" will be reached. When this occurs, the degenerative process becomes irreversible and myofiber necrosis follows.

Degeneration and necrosis represent a continuum of lesions and therefore are often both present within a given lesion. Due to the limited repertoire of skeletal muscle responses, they share similar morphologic features and can thus be difficult to differentiate histologically. This can create a diagnostic challenge. When evaluating a toxicity study, it is important for the pathologist to establish distinct criteria for both lesions and to be consistent and careful when applying them. Criteria should be described in the narrative. The term "myopathy" is commonly used to describe disorders of skeletal muscle in which degeneration and necrosis are key features. However, since myopathy is a general term and one that typically encompasses a collection of lesions rather than one distinct lesion, its use is not recommended.

Recommendations:

When present, myofiber degeneration should be diagnosed and graded. If both degeneration and necrosis are present in a study, the predominant lesion should be diagnosed and the other described in the pathology narrative. However, the pathologist may record both lesions if it best describes the changes that are occurring. Concomitant regeneration should be recorded separately and assigned a severity grade when present to a significant extent. Other secondary lesions, such as inflammation and hemorrhage, should not be diagnosed separately unless warranted by severity but should be described in the narrative.

Related Links:

Skeletal Muscle - Necrosis

References:

Berridge BR, Van Vleet JF, Herman E. 2013. Cardiac, vascular, and skeletal muscle systems. In: Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 3rd ed (Haschek WM, Rousseaux CG, Wallig MA, Bolon B, Ochoa R, Mahler MW, eds). Elsevier, Amsterdam, 1635-1665.

Greaves P. 2007. Musculoskeletal system. In: Histopathology of Preclinical Toxicity Studies, 3rd ed. Elsevier, Oxford, 160-214.

Greaves P, Seely JC. 1996. Non-proliferative lesions of soft tissues and skeletal muscle in rats, MST-1. In: Guides for Toxicologic Pathology. STP/ARP/AFIP, Washington, DC.

Greaves P, Chouinard L, Ernst H, Mecklenburg L, Pruimboom-Brees IM, Rinke M, Rittinghausen S, Thibault S, von Erichsen J, Yoshida T. 2013. Proliferative and non-proliferative lesions of the rat and mouse soft tissue, skeletal muscle, and mesothelium. J Toxicol Pathol 26(3 suppl):1S-26S.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/25035576

Haschek WM, Rousseaux CG, Wallig MA. 2010. Cardiovascular and skeletal muscle systems. In: Fundamentals of Toxicologic Pathology, 2nd ed. Academic Press, San Diego, 319-376.

Leininger JR. 1999. Skeletal muscle. In: Pathology of the Mouse (Maronpot R, Boorman G, Gaul BW, eds). Cache River Press, St Louis, 637-643.

McDonald MM, Hamilton BF. 1990. Bones, joints, and synovia. In: Pathology of the Fischer Rat: Reference and Atlas (Boorman G, Eustis SL, Elwell MR, Montgomery CA, MacKenzie WF, eds). Academic Press, San Diego, 193-207.

Vahle JL, Leininger JR, Long PH, Hall DG, Ernst H. 2013. Bone, muscle, and tooth. In: Toxicologic Pathology: Nonclinical Safety Assessment (Sahota PS, Popp JA, Hardisty JF, Gopinath C, eds). CRC Press, Boca Raton, FL, 561-587.

Van Vleet JF, Valentine BA. 2007. Muscle and tendon. In: Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, 5th ed, Vol 1 (Grant MG, ed). Elsevier, Edinburgh, 185-280.

Weller AH, Magliato SA, Bell KP, Rodenberg NL. 1997. Spontaneous myopathy in the SJL/J mouse: Pathology and strength loss. Muscle Nerve 20:72-82.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/8995586

All Images

Skeletal muscle-Degeneration in a male Harlan Sprague-Dawley rat from a subchronic study. A central myofiber is swollen and hypereosinophilic(arrows), and afragmented segment of another fiber (arrowhead) demonstrates segmental degeneration.

Skeletal muscle-Degeneration in a male Harlan Sprague-Dawley rat from a subchronic study. An enlarged, hypereosinophilic muscle fiber with subtle vacuolation is present in an otherwise normal muscle bundle.

Skeletal muscle-Degeneration in a male Harlan Sprague-Dawley rat from a subchronic study. A rounded fiber contains multiple peripheral nuclei, a single internal nucleus, and abundant cytoplasmic vacuoles.

Skeletal muscle-Degeneration in a male Harlan Sprague-Dawley rat from a subchronic study. Multiple macrophages and interstitial cells have phagocytized degenerative portions of an enlarged muscle fiber.

Skeletal muscle-Degeneration in a male F344/N rat from a chronic study. In this cross section of muscle, several adjacent muscle fibers exhibit multiple features of degeneration;increased sarcolemmal nuclei are indicative of an early regenerative response.

Skeletal muscle-Degeneration in a male Harlan Sprague-Dawley rat from a subchronic study. Degeneration is represented by a swollen, hyalinized, and partly fragmented muscle fiber.

Skeletal muscle-Degeneration in a male Harlan Sprague-Dawley rat from a subchronic study. A fragmented and partly hyalinized muscle fiber has lost its striations and is accompanied by early infiltration of macrophages.

Authors and Reviewers

Authors

Torrie A. Crabbs, DVM, DACVP
Pathologist
Experimental Pathology Laboratories, Inc.
Research Triangle Park, NC  

Reviewers

Philip H. Long, DVM, PhD, DACVP
Presiden and Senior Pathologist
Vet Path Services, Inc.
Mason, OH

Amy Brix, DVM, PhD, DACVP
Senior Pathologist
Experimental Pathology Laboratories, Inc.
Research Triangle Park, NC

Robert R. Maronpot, DVM, MS, MPH, DACVP, DABT, FIATP
Senior Pathologist
Experimental Pathology Laboratories, Inc.
Research Triangle Park, NC