Muscle Aging, Inclusion-Body Myositis and Myopathies

Valerie Askanas, W. King Engel

• Publisher: Wiley-Blackwell
• Year: 2011
• ISBN:
  9781444398298
• Edition: 1
• Topic: Medicina
• Subtopic: Neurología

Muscle weakness with ageing is almost inevitable, generally beginning to manifest beyond the age of 40, and is usually unstoppable. It can lead to reduced mobility, increased risk of falling, injury, and even death. But "you're just getting old" is not a sufficient diagnosis. Specific causes of neuromuscular symptoms may explain progressive muscle weakness, and should be investigated for potential treatment.

Muscle Ageing, Inclusion-Body Myositis and Myopathies explores the clinical and pathological expression of muscle weakness in aging persons. Case studies demonstrate how physicians can more accurately diagnose weakening elderly patients and make better management decisions.

It also explores sporadic inclusion-body myositis and hereditary inclusion-body myopathies. The former, the most common progressive muscle disease in the over 50s, is frequently under-diagnosed and, with the increasing population of aged individuals, is presenting a greater challenge. This disease of muscle has pathological similarities with the well-known Alzheimer and Parkinson brain diseases.

Edited and written by a leading international cast of authors, Muscle Ageing, Inclusion-Body Myositis and Myopathies provides a state-of-the-art guide to ageing-associated neuromuscular disorders. It should be in the hands of all those involved in the care of aging and muscle-weakened patients.

Titles of Related Interest
Neuromuscular Disorders
Tawil and Vennance (eds); ISBN 978-0-470-65456-9

European Handbook of Neurological Management, Vol 1, 2e
Gilhus, Barnes, Brainin (eds); ISBN 978-1-4051-8533-2

European Handbook of Neurological Management, Vol 2, 2e
Gilhus, Barnes, Brainin (eds); ISBN 978-1-4051-8534-9

Part 1: Muscle Aging

Chapter 1

Aging of the Human Neuromuscular System: Pathological Aspects

W. King Engel and Valerie Askanas

Departments of Neurology and Pathology, University of Southern California Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA

Introduction

This chapter discusses both our original findings and concepts, as well as some data of others from the literature. It is not able to cover all aspects of this broad topic. Selected references are presented to stimulate further exploration of the various points discussed.

Succinct Introduction to the Biology of the Neuromuscular System, for Clinicians

Aging persons often have progressive fatigability, weakness, slowness, and general frailty, accompanied by visible atrophy of limb muscles. The weakness frequently is a cause of falling, which can result in serious injury, and sometimes death. Healthy muscle is maintained by: (a) its own salutary trophic metabolic processes; (b) multifactorial trophic influences dispensed from its innervating lower motor neuron (LMN) that are received at each muscle fiber's single neuromuscular junction; and (c) circulating trophic influences. The LMN itself is interdependent both (a) on normal trophic factors from the numerous myelin-containing Schwann cells surrounding its long axonal process like oblong beads on a string, and (b) on retrograde trophic influences acquired from its numerous muscle fibers at the neuromuscular junctions. Each LMN in the human biceps is responsible for activating about 200 muscle fibers and for the continuing trophic nurturing of good health of those muscle fibers. A motor unit refers to one LMN, its Schwann cells, and the muscle fibers it innervates. A neuromuscular disorder, or disease, is one arising from abnormality of any part of the motor unit.

The LMNs and lower sensory neurons have a vital interdependence with the Schwann cells that coat and nurture their axonal extensions: the neurons cannot survive without the Schwann cells, and vice versa. Just as trophic factors “emitting” from LMNs induce and control the special type-1 versus type-2 characteristics of the muscle fibers they innervate, the LMNs probably also induce and maintain hypothetically different sets of “type-1” and “type-2” Schwann cells, respectively, on themselves. And, probably the Schwann cells on sensory neurons are different from ones on motor neurons, because clinically there can be anti-Schwann-cell dysimmune diseases that rather preferentially affect either motor or sensory neurons, and even preferentially involve selectively large-diameter sensory nerve fibers (faster-conducting, conveying position, vibration, and touch sensations) or small-diameter sensory nerve fibers (slower-conducting, conveying pain signals).

A motor unit, with its arborizations, has been likened to a tree, the leaves being compared to the muscle fibers (I think that I shall always see, a motor unit as a tree; with apologies to Joyce Kilmer). In regard to its loss of “leaves,” a tree in autumn, or a waning motor unit, can be affected in toto or in portio [1, 2]. In toto reflects all of the leaves becoming “malnurtured” at about the same time, and in portio is manifested as leaves on the more distal twigs being affected first, showing the first autumnal color changes (as is characteristic of maple trees).

The clinically evident muscle atrophy of elderly persons, which we call atrophy of aging muscle (AAM) (an intentionally general descriptive term), is often assumed to be strictly myogenous (defined as meaning a process involving only muscle, but not LMNs or their peripherally extending axons). However, based on our evidence, it is likely that in a number of circumstances AAM is ultimately neurogenic, i.e. caused by malfunction of the LMNs, or antecedently by impaired trophic influence of the Schwann cells on their LMNs. Because of its clinical, social, and economic importance, AAM will be discussed in regard to some facets of the known and putative malfunctions of the motor unit components, their causes, and their possible treatments.

Note that we use AAM instead of the term sarcopenia. “Sarcopenia” sounds like a definitive diagnosis but it is not. It is often erroneously interpreted as designating a singular pathogenesis. Sarcopenia simply refers, imprecisely, to muscle atrophy in aged animals; it does not indicate or imply any pathogenic mechanism, of which there are a number of possibilities. AAM is usually manifest as type-2 fiber atrophy. A further critique of “sarcopenia” is presented below.

AAM is not a definitive clinical diagnosis, no more than is anemia, or jaundice, or stroke; it is a reason to look carefully, in each individual patient, for a cause, and especially for a treatable cause. Several known causes are described below and in Chapters 2 and 3 in this volume. Whether there is also an as-yet-unidentified general pervasive cause (or causes) that eventually harms the muscles of every aging person is not known. Biochemical studies seeking a general, nearly universal cause typically do not intensively seek, in individual patients and in experimental animals, the possible presence of an identifiable and potentially treatable primary cause (such as peripheral neuropathy, nerve-root radiculopathy, malnutrition, hyperparathyroidism, or a myovascular component).

Aging is a risk factor for AAM, but it is not an ultimate cause. “You're just getting old” is not a cause of AAM, and clinically it certainly should not be used as a dismissive diagnosis of an older patient.

Cellular Aging, in General

Despite a vast literature on cellular aging, the causes and mechanisms are still poorly understood, and treatment non-existent. Mature, post-mitotic muscle fibers, similarly to post-mitotic neurons, seem to be more susceptible to a chronic cellular aging than are dividing cells. Cellular aging involves abnormalities of various subcellular aspects, such as nuclei, mitochondria, endoplasmic reticulum, Golgi, and structural and aqueous components. Proteasome and lysosome degradations are especially important. Oxidative stress and endoplasmic reticulum stress are also proposed to play important roles. The “proteome” designates the large and varied family of proteins of a cell, the profile of which is cell-type-specific.

One can wonder whether the general aging changes of cells are due to effects of a still-obscure omnipotent ”master vitalostat,” such as a “master gene” acting like a rheostat that gradually turns down the vitality of the cell. If there is a master vitalostat. What initiates the turning-down, what are the key steps by which it executes that turndown, and how can it be controlled? What are the underlying genetic factors, and/or important epigenetic mechanisms? (Philosophically, why are all living creatures programmed from “conception” to die?) In the atrophy process, there might be multiple stages and pathways participating, some of which, if identifiable, could become amenable to not-yet-developed treatments. Hypothetically, for skeletal muscle there might be at least two so-called master genes, Fiber2atrophin and Fiber1atrophin, that are normally inhibited, but when activated by an atrophy-promoting factor they instigate cascades of other genetic activations and inhibitions, resulting in preferential atrophy of type-2 or type-1 muscle fibers respectively. Preferential type-2 fiber atrophies are discussed below. (Preferential atrophy of type-1 fibers is seen in myotonic dystrophy type-1, a disease caused by expansion of CTG trinucleotide repeats of the gene DMPK; and in preferential “congenital type-1 fiber hypotrophy with central nuclei” [3], which in some patients is attributable to a genetic mutation of myotubularin, myogenic-factor-6, or dynamin-1.)

Some Unanswered Questions

Is the muscle frailty associated with AAM universally inevitable, like the aging-related, more-visible frailty and atrophy of skin, like the failure of estrogen in menopausal women and the gradual petering-out of testosterone in aging men, like scalp follicles disappearing or producing only non-pigmented hairs, like vascular sclerosis, like accumulation of “wear-and-tear” lipofuscin pigment within lower-motor neurons, other neurons, and muscle fibers? What is the most essential mechanism that starts and perpetuates AAM? Is it something we all ingest, or do not ingest; is it the cumulative solar or cosmic irradiation, or Mother Earth's constant radon emission; or perhaps there is something else to which we all are exposed? Is there a gradual cellular accumulation of something cumulatively more toxic than the accumulating lipofuscin – such as oxidatively damaged or otherwise-toxified misfolded proteins – that gradually “rusts” beneficent cellular functions and activates “atrophy processes”? Why can't any of the pathogenic mechanisms putatively contributing to AAM be prevented or treated now? Much work needs to be done before we can prescribe an elixir to make the elderly intellectually brilliant and vigorous.

Indefinable are the terms “normal aged person” or “normal-control aged person.” In muscle biopsies of aging persons we nearly always have observed different combinations and various degrees of denervation atrophy and/or type-2 fiber atrophy (see below).

Neuromuscular Histology

Normal skeletal muscle is the most abundant of human tissues. It is composed of muscle fibers that are very long cylinders. Their length is about 1000 times their typical diameter of about 45–65 μm (in the biceps). Transverse histochemical sections of muscle biopsies are diagnostically more informative than longitudinal ones. The universally used stain for general evaluation of muscle-biopsy histochemistry is the Engel trichrome [4, 5]. (It stains myofibrils green and their Z-disks red; mitochondria, t-tubules, longitudinal endoplasmic reticulum, and plasmalemma red; and DNA and RNA dark blue. It also stains the protein component of Schwann cell myelin red and neuronal axons green.) The histochemical types of human muscle fibers are most distinctively delineated by two myofibrillar ATPase reactions: (a) the regular ATPase (reg-ATPase) incubated at pH 9.4 [6], and (b) the acid-preincubated reverse-ATPase (rev-ATPase) [7]. (Some myopathologists also use antibodies against different types of myosin for fiber-type definition.) In normal adult human and mammalian animal muscle, fibers lightly stained with reg-ATPase and reciprocally dark with rev-ATPase are arbitrarily designated type-1 fibers [4, 7–10], while the fibers oppositely stained are type-2 fibers. The type-1 fibers are high in most of the mitochondrial oxidative-enzyme activities (e.g. cytochrome oxidase (COX), succinate dehydrogenase (SDH), and hydroxybutyrate dehydrogenase), as well as myoglobin and triglyceride droplets; and they are low in the anerobic glycolysis enzymes myophosphorylase and UDPG-glycogen transferase, in glycogen, and in the aqueous sarcoplasmic enzyme lactate dehydrogenase. The type-2 fibers are oppositely stained with those reactions...

Table of contents

• Cover
• Title Page
• Copyright
• List of Contributors
• Preface
• Part 1: Muscle Aging
• Part 2: Sporadic Inclusion-Body Myositis
• Part 3: Hereditary Inclusion-Body Myopathies
• Index
• Plate section facing