Skeletal muscle: ageing and disease Flashcards
List the factors that control muscle mass?
Nutritional status
Hormones
Genetics
Innervation
Inflammation
Oxidative stress
Blood flow
Exercise
Disease
Protein synthesis and degradation
What are the three fibre types present in muscle?
Fast fatiguable
Fast resistant
Slow
Describe the difference in twitch responses between FF, FR and S muscle fibres?
FF: fast twitch
FR: fast twitch
S: slow twitch
Describe the difference in fatiguability between FF, FR and S muscle fibres?
FF: fatigue rapidly
FR: fatigue slowly
S: do not fatigue
Describe the concept of muscle fibre malleability?
Fibres exist as either pure (one type of MHC) or hybrids (multiple forms of MHC)
What determines the composition of MHC in a muscle fibre?
Varies according to stimuli
Composition reflects function
What are the goals of intervention to attenuate muscle wasting?
Attenuate muscle atrophy
Promote muscle strength
NOT: increase muscle fatigue
Give an example of a genetic influence on muscle mass?
Myostatin: negative regulator of muscle mass
Knockout > increase muscle mass
Describe the situtations which may lead to disuse muscle atrophy?
Hindlimb underweighting
Immobilisation
Limb casting
Prolonged bed rest
Spaceflight
Describe the effect of denervation on muscle mass?
Denervation atrophy
Describe cancer cachexia?
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
Loss of how much muscle mass is fatal?
40%
Describe why muscle wasting is thought to occur so rapidly in the ICU?
How is this being combatted?
Inflammatory environment > cascade of signalling pathways > favour protein degradation
Occurs over days
Treatment with electrical stimulation and exercise in the ICU
Describe the outcome of loss of muscle mass in disease states and old age?
Compromises QoL and survival
Describe sarcopenia?
Age-associated loss of skeletal muscle mass and function
Describe the cause of sarcopenia?
Multifactorial: disuse, endocrine changes, chronic diseases, inflammation, insulin resistance, nutritional deficiencies
In which patients should a diagnosis of sarcopenia be considered?
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
Describe the functional effects of sarcopenia?
Descreased running performance
Descreased performace in explosive events
Eventually impacts upon personal care, feeding and domestic duties
Describe the changes that occur in muscle during sarcopenia?
Decreased muscle mass
Increased connectove tissue and fat
Define weakness?
Inability to develop an initial force appropriate for the circumstances
At what age does loss of muscle strength usually onset?
50
Which muscle types are most affected by sarcopenia?
Fast muscles more affected than slow
Describe the effect muscle fibre denervation and reinnervation with a new fibre type?
Muscle fibre changes to match new innervation
Describe the chnages in speed of contraction that occur with ageing?
When do these changes occur?
Changes in Ca handling (impaired release and reuptake) > speed of contraction affected
Occurs before severe muscle wasting
Describe how motoneuron losses in ageing are handled?
Type IIB fibres most susceptible > may be renervated by axonal sprouting from slow fibres, or may cease functioning
Describe the changes that are thought to occur in motoneurons with ageing?
Demyelination
Remodelling of motor end plates
Increased connective tissue
Smaller diameter axons
Are the changes that occur in sarcopenia reversilbe?
Can they be attenuated?
Generally not reversible
Can be attenuated with strength training
Describe the effects of strength training in the elderly?
Significant increase in muscle strength
Significant hypertrophy
Increase lean total body mass
Increase in muscle fibre area
What are the adaptations that occur in strength training in the elderly thought to be an effect of?
Combination of neural adaptations and muscle hypertrophy
Describe the hormonal changes that occur with ageing that may have an effect on muscle mass and strength?
Decreased circulating levels of anabolic hormones: GH, IGF-1, testosterone
Compromises efficiency of muscle regeneration and repair
Describe the age of onset of DMD?
2-6 years
Describe the inheritance of DMD?
X-linked recessive
Describe the pattern of onset of DMD?
Generalised weakness and muscle wasting affecting limb and trunk muscles first
Calves often enlarged
Progresses to affect all voluntary muscles
Why are the calves enlarged in the initial stages of DMD?
During early stages, muscles are breaking down and repairing well
Fewer fibres are present, but they are hypertrophied
Describe the clinical features of DMD?
Lordotic and waddling gait
Gower’s sign
Describe the changes in the muscle that occur during DMD?
Loss of fibres
Variable fibre size
Infiltration of fibrosis
What is the cause of DMD?
Mutation in dystrophin gene on Xp21 > deficiency in dystrophin expression
Describe the dystrophin-glycoprotein complex?
Describe the physiological role of dystrophin?
Structural role in stabilising sarcolema during muscle contraction
Also a receiver and transducer of signals
Describe the age of onset of BMD?
Adolescence or adulthood
How do the symptoms and presentation of BMD differ from DMD?
Almost identical, but less severe
Significant heart involvements
Describe how the cause of BMD differs to DMD?
X linked recessive mutation in dystrophin gene, but some dystrophin still produced
Many abnormal, smaller molecules
Also some larger, useful proteins
Describe the effect of loss of dystrophin on myofibre function and organisation?
Disorganised costameres > enhanced membrane leak
Increased oedema
Inappropriate cystolic Ca and ROS generation
Increased ECM deposition
Describe the effect of costamere dysfunction on force transmission?
Muscle contraction > no force transmission
Are dystrophic muscles more susceptible to contraction induced injury?
Why/why not?
There is support for this hypothesis
Membrane disruption allows influx of Ca, leads to hypercontraction and necrosis
High incidence of branching
Describe the biochemical signs of DMD and BMD?
Elevated serum CK (marker of muscle damage)
Increased Evans blue dye uptake (membrane disruption)
Describe the treatment targets of muscular dystrophy?
Correct genetic defect (gene therapy)
Cell therapy (myoblast transfer, stem cells)
Prevention of secondary consequences (corticosteroids)
