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Question

Difficulty: MediumCellular Injury and Adaptation

A 72-year-old woman is brought to the clinic by her son for a routine follow-up. She has a history of a massive ischemic stroke 8 months ago involving the right middle cerebral artery territory, which resulted in dense left-sided hemiplegia. Since the stroke, she has been bedbound and non-weight-bearing on her left side despite physical therapy efforts. Her current medications include aspirin, atorvastatin, and lisinopril. On physical examination, her vital signs are within normal limits. There is marked asymmetry of her lower extremities; her left thigh and calf circumferences are significantly smaller than those on the right. Deep tendon reflexes are 3+ on the left and 2+ on the right, with a positive Babinski sign on the left. The skin on the left leg is intact with no erythema, edema, or calf tenderness. Which of the following subcellular processes is most directly responsible for the reduction in muscle mass observed in this patient's left lower extremity?

  1. A
    Opening of the mitochondrial permeability transition pore and cytosolic release of cytochrome c
  2. B
    Intravascular fibrin polymerization and platelet aggregation causing microvascular hypoxic injury
  3. Covalent attachment of ubiquitin to cytoskeletal proteins and subsequent proteasomal degradationAnswer
  4. D
    Pharmacological depletion of intracellular isoprenoids leading to myocyte mitochondrial dysfunction
  5. E
    Massive influx of extracellular calcium activating cytosolic phospholipases and endonucleases

Answer

Covalent attachment of ubiquitin to cytoskeletal proteins and subsequent proteasomal degradation
The patient's presentation of a unilaterally smaller limb 8 months after a hemiplegic stroke is classic for disuse atrophy. When skeletal muscle experiences a prolonged decrease in workload or loss of innervation, it undergoes atrophy to adapt to the reduced demand. This reduction in cell size and mass is achieved through a combination of decreased protein synthesis and increased protein degradation. The primary mechanism of protein degradation in atrophic muscle is the ubiquitin-proteasome pathway, where cytoskeletal proteins are tagged with ubiquitin and subsequently degraded by proteasomes.

Step-by-Step Solution

1
Analyze the patient's history and physical examination findings.
The patient has a history of left-sided hemiplegia for 8 months following a stroke, with significantly reduced muscle mass in the paralyzed left leg compared to the normal right leg, and no signs of acute inflammation or vascular compromise.
Establishes the clinical diagnosis of disuse atrophy secondary to an upper motor neuron lesion.
2
Identify the cellular adaptation occurring in the affected tissue.
The skeletal muscle fibers are undergoing atrophy (reduction in cell size and mass) to adapt to the loss of workload and neurological input.
Connects the clinical presentation to the underlying pathological adaptation.
3
Determine the subcellular mechanism driving this adaptation.
Atrophy is primarily mediated by decreased protein synthesis and increased protein degradation, largely through the ubiquitin-proteasome pathway.
Directly answers the specific mechanism requested by the question stem.

Key Concept

Disuse atrophy of skeletal muscle is characterized by a reduction in cell size and mass, primarily driven by the degradation of cytoskeletal proteins via the ubiquitin-proteasome pathway.
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Topics

Cellular Injury and Adaptation

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