Fiber Typing in Aging Muscle

Fennigje M. Purves-Smith; Nicolas Sgarioto; Russell T. Hepple

Disclosures

Exerc Sport Sci Rev. 2014;42(2):45-52. 

In This Article

Abstract and Introduction

Abstract

It is accepted widely that fast-twitch muscle fibers are preferentially impacted in aging muscle, yet we hypothesize that this is not valid when aging muscle atrophy becomes severe. In this review, we summarize the evidence of fiber type-specific effect in aging muscle and the potential confounding roles of fibers coexpressing multiple myosin heavy-chain isoforms and their histochemical identification.

Introduction

A preferential fast-twitch (Type II) fiber involvement is among the most widely accepted features of aging muscle and informs many of the therapeutic approaches to this problem of aging, yet the rigor of this view should be closely scrutinized because of the complexity of classifying fiber type in advanced age when many individual muscle fibers express multiple myosin heavy-chain (MHC) isoforms simultaneously (MHC coexpressing fibers).[1,10,26,30,33] As will be discussed, denervation is the primary event responsible for producing these MHC coexpressing fibers in aging muscle[30] and not only do they pose a challenge in terms of their histological identification, but understanding whether they are derived from formerly pure slow (Type I) or pure fast (Type II) fibers has a critical role in accurately assessing the degree to which fast versus slow fibers are affected in aging muscle (Fig. 1). It also is important to stress that the abundance of these MHC coexpressing fibers increases dramatically at more advanced ages (≥80 yr)[1] where denervated fibers are common[30,31] (Fig. 2) and aging muscle atrophy is most likely to have clinical impact.[13] Thus, the impact of the MHC coexpressing phenomenon is greatest at clinically relevant ages (≥80 yr), underscoring the importance of understanding how this phenomenon may obscure identification of fiber type-specific behavior in aging muscle.

Figure 1.

Schematic diagram showing how denervation can result in the generation of muscle fibers that coexpress multiple myosin heavychain (MHC) isoforms. In the context of aging, the problem of MHC coexpression is twofold. First, not all methods of fiber typing are well suited to identifying MHC coexpressing fibers particularly when aging muscle atrophy becomes severe and MHC coexpressing fibers are in high abundance. Second, understanding the atrophy behavior of specific fiber types is contingent upon understanding from which parent fiber population the MHC coexpressing fibers originate because these coexpressing fibers are frequently extremely atrophied.

Figure 2.

Photomicrographs of human muscle labeled with fiber type-specific myosin heavy-chain (MHC) antibodies. (A) Healthy adult (20- to 25-yr-old) muscle; (B) old (70- to 75-yr-old) muscle; (C) very old (≥80 yr) muscle. Note that not only is the nature of fiber atrophy different across the aging continuum, where old age is associated with relatively uniform atrophy across fiber types, whereas very old age is associated with a marked accumulation of small angular fibers (white arrows), but very old age also is associated with an accumulation of MHC coexpressing fibers (grey (red) arrows) that also are usually small and angular — traits typical of denervated myofibers. [Adapted from information in (6).]

To illustrate how these issues can confound our understanding of fiber type-specific effect in aging muscle, consider a hypothetical situation where MHC slow-fast coexpressing fibers originate from formerly pure slow fibers and that their identity is misclassified as fast fibers. In this situation, the atrophy behavior of what were formerly pure slow fibers is incorrectly ascribed to the fast fiber population. Although it is not possible to determine the degree to which this situation has occurred in previous assessments of fiber type changes in aging muscle, we hypothesize that this situation has high potential to adversely impact our understanding of fiber type-specific changes in aging muscle at clinically relevant ages (i.e., when muscle atrophy becomes severe enough to cause an increase in falls and impair mobility). Consistent with this hypothesis, as will be shown in this review, recent reassessment of the atrophy behavior of slow fibers in aging muscle using methods well suited to identification of MHC coexpressing fibers, and which used a strategy for tracking the origins of these slow-fast coexpressing fibers, has revealed a marked slow fiber atrophy potential in very advanced age that has not been described previously.[26,30] In view of this behavior, we also address in this review whether there are circumstances where formerly pure slow fibers that transition to slow-fast coexpressing fibers in aging muscle could be misclassified as fast fibers. In this latter respect, we show that use of myofibrillar adenosine triphosphatase (mATPase) histochemistry to classify fiber types in aging muscle is a method particularly vulnerable to this problem. Thus, the purpose of this review is to revisit the evidence for preferential fast fiber involvement with aging, to account for how the phenomenon of MHC slow-fast coexpression can obscure our understanding, and finally to evaluate the potential for mATPase histochemistry to cause misclassification of MHC coexpressing fibers in aging muscle. The most important outcome of this review is that we conclude, at ages where muscle atrophy severity is most likely to have clinical impact, the pursuit of treatments for aging muscle atrophy needs to consider the involvement of both slow and fast fibers because both are impacted significantly at advanced age.

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