Skeletal Muscle and Ageing Flashcards
List 7 conditions associated with muscle wasting
Disuse atrophy (e.g. with plaster casting, bed rest)
Denervation
Sepsis
HIV/AIDs
Ageing (sarcopenia)
Cancer cachexia
Muscular dystrophy and other muscle diseases
Describe the different compositions of muscles as they reflect their different functions
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
Explain the concept of muscle fibre malleability
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
Contrast the muscle fibre composition of the soleus vs. the extraocular muscles
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
What should the goals of intervention to attenuate muscle wasting be?
To attenuate muscle atrophy and promote muscle strength without increasing muscle fatigue
What is the relationship between muscle size and myostatin?
Low or absent myostatin causes muscle hypertrophy (myostatin acts as a negative regulator of muscle mass)
What impact does cancer cachexia have on treatment and prognosis?
Impairs response to chemo- and radio-therapy
>20% of cancer-related deaths due to cancer cachexia
What % loss of muscle mass is fatal?
~40%
What are the microscopic abnormalities in cancer cachexia?
Atrophy and disruption of the normal architecture
What is the underlying abnormality in critical illness myopathy?
Inflammatory environment induces a cascade of signalling resulting in protein degradation in muscle
What is the underlying pathology in sarcopenia?
Multifactorial causes (disuse, changing endocrine function, chronic diseases, inflammation, insulin resistance, nutritional deficiencies)
When should sarcopenia be considered?
In patients who are bedridden, cannot independently rise from a chair, or who have a measured gait <1.0m/s
What are the diagnostic criteria for sarcopenia?
Gait speed <2SD of the average of a young adult (as measured with DEXA)
What is the definition of sarcopenia as used by the European Working Group on Sarcopenia in Older People?
Low muscle mass, AND
Low muscle strength OR low physical performance
Define weakness in the context of muscle wasting
Inability to develop an initial force appropriate for the circumstances
At what age does the sudden decline in muscle strength begin?
50
Which muscle fibres are preferentially affected in sarcopenia? Why is this?
Type IIb (fast-twitch) Due to selective loss of motor units
Describe the process of age-related motor unit remodelling
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
Are motor units or just muscle fibres lost with age?
Both
What occurs simultaneously with loss of muscle mass in sarcopenia?
Accumulation of connective tissue (including fibronectin) and fat
What causes the slowing of contraction in sarcopenia and when does this occur on the timeline of disease?
Slowing of contraction occurs before severe muscle wasting
Caused by age-related impairments in release and reuptake of Ca2+
What is the impact of ageing on neuromuscular function and how might this contribute to sarcopenia?
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)
Why is the ability of muscle to repair itself impaired with ageing?
Due to loss of satellite cells
What is the role of IGF-1 in muscle function?
Responsible for maintaining muscle mass
Which of the two major dystrophinopathies is more severe? What is responsible for this difference in severity?
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
What is the age of onset in DMD?
2-6 years
What are the symptoms of DMD?
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)
What is the prognosis of DMD?
Wheelchair dependent at age 7-13
Survival rare beyond late 20s (death due to cardiorespiratory failure)
What is the genetic basis of DMD and BMD?
X-linked recessive mutation in the dystrophin gene located at Xp21
Affects boys only, females are carriers
What is the normal function of dystrophin?
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
A mutation in what protein causes congenital MD?
Laminin
A mutation in what proteins causes limb girdle MD?
Proteins in the sarcoglycan complex
What is the age of onset in BMD?
Adolescence or adulthood
What are the symptoms of BMD?
Generalised weakness and muscle wasting affecting limb and trunk muscles first
Pseudo-hypertrophy of calves
May be significant heart involvements
What is the prognosis of BMD?
Slow progression with variable course
Will eventually affect all voluntary muscles
Survival well into mid-late adulthood
What is a costamere?
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)
What is the result of loss of dystrophin on a cellular level?
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
What does the elevation of intracellular Ca2+ signal in muscle fibres?
Pathways for the breakdown of muscle fibre
