Skeletal Muscle and Ageing

Question 1

List 7 conditions associated with muscle wasting

Answer 1

Disuse atrophy (e.g. with plaster casting, bed rest)
Denervation
Sepsis
HIV/AIDs
Ageing (sarcopenia)
Cancer cachexia
Muscular dystrophy and other muscle diseases

Question 2

Describe the different compositions of muscles as they reflect their different functions

Answer 2

Larger, faster muscle fibres provide high force but fatigue quickly
Moderate muscle fibres produce moderate force and are reasonably resistant to fatigue
Smaller, slower muscle fibres produce lower forces but are more resistant to fatigue

Question 3

Explain the concept of muscle fibre malleability

Answer 3

Fibres exist as either “pure” (with 1 type of myosin) or as hybrids containing multiple forms
Fibres are able to change their properties in respond to stimulus

Question 4

Contrast the muscle fibre composition of the soleus vs. the extraocular muscles

Answer 4

Soleus is a postural muscle and therefore predominantly contains slow-contracting type I (B-cardiac) fibres, with some type IIa and IIx
Extraocular muscles perform a variety of roles including rapid movements (saccades) and fixed gaze; to reflect their variable function they contain a variety of different myosin types

Question 5

What should the goals of intervention to attenuate muscle wasting be?

Answer 5

To attenuate muscle atrophy and promote muscle strength without increasing muscle fatigue

Question 6

What is the relationship between muscle size and myostatin?

Answer 6

Low or absent myostatin causes muscle hypertrophy (myostatin acts as a negative regulator of muscle mass)

Question 7

What impact does cancer cachexia have on treatment and prognosis?

Answer 7

Impairs response to chemo- and radio-therapy

>20% of cancer-related deaths due to cancer cachexia

Question 8

What % loss of muscle mass is fatal?

Answer 8

~40%

Question 9

What are the microscopic abnormalities in cancer cachexia?

Answer 9

Atrophy and disruption of the normal architecture

Question 10

What is the underlying abnormality in critical illness myopathy?

Answer 10

Inflammatory environment induces a cascade of signalling resulting in protein degradation in muscle

Question 11

What is the underlying pathology in sarcopenia?

Answer 11

Multifactorial causes (disuse, changing endocrine function, chronic diseases, inflammation, insulin resistance, nutritional deficiencies)

Question 12

When should sarcopenia be considered?

Answer 12

In patients who are bedridden, cannot independently rise from a chair, or who have a measured gait <1.0m/s

Question 13

What are the diagnostic criteria for sarcopenia?

Answer 13

Gait speed <2SD of the average of a young adult (as measured with DEXA)

Question 14

What is the definition of sarcopenia as used by the European Working Group on Sarcopenia in Older People?

Answer 14

Low muscle mass, AND

Low muscle strength OR low physical performance

Question 15

Define weakness in the context of muscle wasting

Answer 15

Inability to develop an initial force appropriate for the circumstances

Question 16

At what age does the sudden decline in muscle strength begin?

Answer 16

50

Question 17

Which muscle fibres are preferentially affected in sarcopenia? Why is this?

Answer 17

Type IIb (fast-twitch)
Due to selective loss of motor units

Question 18

Describe the process of age-related motor unit remodelling

Answer 18

Denervation of type II motor units results in atrophy (and some death) of these fibres and decreased muscle mass
Subsequent reinnervation with type I motor units (due to axonal sprouting of these neighbouring motoneurons) changes the previously type II fibres to slow type I fibres
Higher proportion of slow fibres in aged muscle and reduction in muscle mass due to death of some fibres

Question 19

Are motor units or just muscle fibres lost with age?

Answer 19

Both

Question 20

What occurs simultaneously with loss of muscle mass in sarcopenia?

Answer 20

Accumulation of connective tissue (including fibronectin) and fat

Question 21

What causes the slowing of contraction in sarcopenia and when does this occur on the timeline of disease?

Answer 21

Slowing of contraction occurs before severe muscle wasting

Caused by age-related impairments in release and reuptake of Ca2+

Question 22

What is the impact of ageing on neuromuscular function and how might this contribute to sarcopenia?

Answer 22

Possible demyelination could affect neurotransmission and slow action potential propagation
Motor end plates undergo continuous remodelling including widening of the end plate, longer nerve terminals and fewer side branches (compensatory but eventually unsuccessful)

Question 23

Why is the ability of muscle to repair itself impaired with ageing?

Answer 23

Due to loss of satellite cells

Question 24

What is the role of IGF-1 in muscle function?

Answer 24

Responsible for maintaining muscle mass

Question 25

Which of the two major dystrophinopathies is more severe? What is responsible for this difference in severity?

Answer 25

Duchenne Muscular Dystrophy (DMD) more severe
Complete (DMD) vs. partial (Becker Muscular Dystrophy, BMD) loss of dystrophin (retained dystrophin in BMD is abnormal and smaller)
DMD involves “frame shift” mutation and synthesis of very small, unstable fragments
Mutations in BMD preserves the reading frame to produce useful portions of dystrophin

Question 26

What is the age of onset in DMD?

Answer 26

2-6 years

Question 27

What are the symptoms of DMD?

Answer 27

Generalised weakness and muscle wasting affecting limb and trunk muscles first
Pseudo-hypertrophy of calves (initially)
Abnormal spinal curvature with exaggerated lumbar lordosis and thoracic kyphosis
Waddling gait
Developmental delay
Short stature
Gowers sign (patients “walk” themselves up off the floor)

Question 28

What is the prognosis of DMD?

Answer 28

Wheelchair dependent at age 7-13

Survival rare beyond late 20s (death due to cardiorespiratory failure)

Question 29

What is the genetic basis of DMD and BMD?

Answer 29

X-linked recessive mutation in the dystrophin gene located at Xp21
Affects boys only, females are carriers

Question 30

What is the normal function of dystrophin?

Answer 30

Protein found on cytoplasmic surface of fibres and associated with dystrophin-associated protein (DAP) complex or dystrophin-glycoprotein complex (DGC)
Interacts with cytoskeleton via F-actin and anchors the contractile apparatus externally through laminin to stabilise the sarcolemma during contraction (especially in lengthening actions)
Also postulated to play a role in anabolic signalling to muscles

Question 31

A mutation in what protein causes congenital MD?

Answer 31

Laminin

Question 32

A mutation in what proteins causes limb girdle MD?

Answer 32

Proteins in the sarcoglycan complex

Question 33

What is the age of onset in BMD?

Answer 33

Adolescence or adulthood

Question 34

What are the symptoms of BMD?

Answer 34

Generalised weakness and muscle wasting affecting limb and trunk muscles first
Pseudo-hypertrophy of calves
May be significant heart involvements

Question 35

What is the prognosis of BMD?

Answer 35

Slow progression with variable course
Will eventually affect all voluntary muscles
Survival well into mid-late adulthood

Question 36

What is a costamere?

Answer 36

Rib-like lattices formed on the cytoplasmic face of the sarcolemma by DCG
Form mechanical links between sarcomeres in the muscle fibre and laminin in the ECM (confers stability when stretched)

Question 37

What is the result of loss of dystrophin on a cellular level?

Answer 37

Costameres are disorganised and this results in membrane tear and leak upon stretching of muscle
Increased oedema and inappropriate cytosolic Ca2+ leads to ROS generation and muscle dysfunction
There is also increased ECM deposition around myofibres

Question 38

What does the elevation of intracellular Ca2+ signal in muscle fibres?

Answer 38

Pathways for the breakdown of muscle fibre