Skeletal muscle: ageing and disease

Question 1

List the factors that control muscle mass?

Answer 1

Nutritional status

Hormones

Genetics

Innervation

Inflammation

Oxidative stress

Blood flow

Exercise

Disease

Protein synthesis and degradation

Question 2

What are the three fibre types present in muscle?

Answer 2

Fast fatiguable

Fast resistant

Slow

Question 3

Describe the difference in twitch responses between FF, FR and S muscle fibres?

Answer 3

FF: fast twitch

FR: fast twitch

S: slow twitch

Question 4

Describe the difference in fatiguability between FF, FR and S muscle fibres?

Answer 4

FF: fatigue rapidly

FR: fatigue slowly

S: do not fatigue

Question 5

Describe the concept of muscle fibre malleability?

Answer 5

Fibres exist as either pure (one type of MHC) or hybrids (multiple forms of MHC)

Question 6

What determines the composition of MHC in a muscle fibre?

Answer 6

Varies according to stimuli

Composition reflects function

Question 7

What are the goals of intervention to attenuate muscle wasting?

Answer 7

Attenuate muscle atrophy

Promote muscle strength

NOT: increase muscle fatigue

Question 8

Give an example of a genetic influence on muscle mass?

Answer 8

Myostatin: negative regulator of muscle mass

Knockout > increase muscle mass

Question 9

Describe the situtations which may lead to disuse muscle atrophy?

Answer 9

Hindlimb underweighting

Immobilisation

Limb casting

Prolonged bed rest

Spaceflight

Question 10

Describe the effect of denervation on muscle mass?

Answer 10

Denervation atrophy

Question 11

Describe cancer cachexia?

Answer 11

Severe wasting and weakness in many cancer patients

Disruption of muscle architecture

Affects up to 80% lung, pancreatic and GIT cancer patients

Reduces QoL

Impairs response to chemo and radiotherapy

Question 12

Loss of how much muscle mass is fatal?

Answer 12

40%

Question 13

Describe why muscle wasting is thought to occur so rapidly in the ICU?

How is this being combatted?

Answer 13

Inflammatory environment > cascade of signalling pathways > favour protein degradation

Occurs over days

Treatment with electrical stimulation and exercise in the ICU

Question 14

Describe the outcome of loss of muscle mass in disease states and old age?

Answer 14

Compromises QoL and survival

Question 15

Describe sarcopenia?

Answer 15

Age-associated loss of skeletal muscle mass and function

Question 16

Describe the cause of sarcopenia?

Answer 16

Multifactorial: disuse, endocrine changes, chronic diseases, inflammation, insulin resistance, nutritional deficiencies

Question 17

In which patients should a diagnosis of sarcopenia be considered?

Answer 17

All older patients with observed declines in physical function, strength or overall health

Bedridden, cannot rise from a chair or measured gait speed <1 m/s

Question 18

Describe the functional effects of sarcopenia?

Answer 18

Descreased running performance

Descreased performace in explosive events

Eventually impacts upon personal care, feeding and domestic duties

Question 19

Describe the changes that occur in muscle during sarcopenia?

Answer 19

Decreased muscle mass

Increased connectove tissue and fat

Question 20

Define weakness?

Answer 20

Inability to develop an initial force appropriate for the circumstances

Question 21

At what age does loss of muscle strength usually onset?

Answer 21

50

Question 22

Which muscle types are most affected by sarcopenia?

Answer 22

Fast muscles more affected than slow

Question 23

Describe the effect muscle fibre denervation and reinnervation with a new fibre type?

Answer 23

Muscle fibre changes to match new innervation

Question 24

Describe the chnages in speed of contraction that occur with ageing?

When do these changes occur?

Answer 24

Changes in Ca handling (impaired release and reuptake) > speed of contraction affected

Occurs before severe muscle wasting

Question 25

Describe how motoneuron losses in ageing are handled?

Answer 25

Type IIB fibres most susceptible \> may be renervated by axonal sprouting from slow fibres, or may cease functioning

Question 26

Describe the changes that are thought to occur in motoneurons with ageing?

Answer 26

Demyelination Remodelling of motor end plates Increased connective tissue Smaller diameter axons

Question 27

Are the changes that occur in sarcopenia reversilbe? Can they be attenuated?

Answer 27

Generally not reversible Can be attenuated with strength training

Question 28

Describe the effects of strength training in the elderly?

Answer 28

Significant increase in muscle strength Significant hypertrophy Increase lean total body mass Increase in muscle fibre area

Question 29

What are the adaptations that occur in strength training in the elderly thought to be an effect of?

Answer 29

Combination of neural adaptations and muscle hypertrophy

Question 30

Describe the hormonal changes that occur with ageing that may have an effect on muscle mass and strength?

Answer 30

Decreased circulating levels of anabolic hormones: GH, IGF-1, testosterone Compromises efficiency of muscle regeneration and repair

Question 31

Describe the age of onset of DMD?

Answer 31

2-6 years

Question 32

Describe the inheritance of DMD?

Answer 32

X-linked recessive

Question 33

Describe the pattern of onset of DMD?

Answer 33

Generalised weakness and muscle wasting affecting limb and trunk muscles first Calves often enlarged Progresses to affect all voluntary muscles

Question 34

Why are the calves enlarged in the initial stages of DMD?

Answer 34

During early stages, muscles are breaking down and repairing well Fewer fibres are present, but they are hypertrophied

Question 35

Describe the clinical features of DMD?

Answer 35

Lordotic and waddling gait Gower's sign

Question 36

Describe the changes in the muscle that occur during DMD?

Answer 36

Loss of fibres Variable fibre size Infiltration of fibrosis

Question 37

What is the cause of DMD?

Answer 37

Mutation in dystrophin gene on Xp21 \> deficiency in dystrophin expression

Question 38

Describe the dystrophin-glycoprotein complex?

Answer 38

Question 39

Describe the physiological role of dystrophin?

Answer 39

Structural role in stabilising sarcolema during muscle contraction Also a receiver and transducer of signals

Question 40

Describe the age of onset of BMD?

Answer 40

Adolescence or adulthood

Question 41

How do the symptoms and presentation of BMD differ from DMD?

Answer 41

Almost identical, but less severe Significant heart involvements

Question 42

Describe how the cause of BMD differs to DMD?

Answer 42

X linked recessive mutation in dystrophin gene, but some dystrophin still produced Many abnormal, smaller molecules Also some larger, useful proteins

Question 43

Describe the effect of loss of dystrophin on myofibre function and organisation?

Answer 43

Disorganised costameres \> enhanced membrane leak Increased oedema Inappropriate cystolic Ca and ROS generation Increased ECM deposition

Question 44

Describe the effect of costamere dysfunction on force transmission?

Answer 44

Muscle contraction \> no force transmission

Question 45

Are dystrophic muscles more susceptible to contraction induced injury? Why/why not?

Answer 45

There is support for this hypothesis Membrane disruption allows influx of Ca, leads to hypercontraction and necrosis High incidence of branching

Question 46

Describe the biochemical signs of DMD and BMD?

Answer 46

Elevated serum CK (marker of muscle damage) Increased Evans blue dye uptake (membrane disruption)

Question 47

Describe the treatment targets of muscular dystrophy?

Answer 47

Correct genetic defect (gene therapy) Cell therapy (myoblast transfer, stem cells) Prevention of secondary consequences (corticosteroids)