Biochemical and pathological changes result from mutated Caveolin-3 in muscle

Area of Science:

• Muscle biology
• Cellular pathology
• Molecular genetics

Background:

• Caveolin-3 (CAV3) is a muscle protein crucial for sarcolemmal integrity and ECM-cytoskeleton connection.
• Mutations in CAV3 cause caveolinopathies, often linked to elevated CK levels and sarcolemmal damage.
• The p.P104L mutation is known to cause Golgi retention and ER stress, but downstream effects were unclear.

Purpose of the Study:

• To systematically investigate the molecular and subcellular consequences of the CAV3 p.P104L mutation in a mouse model.
• To elucidate the downstream pathophysiological events in p.P104L caveolinopathy.

Main Methods:

• Utilized a transgenic p.P104L mutant mouse model.
• Performed proteomic profiling, immunoprecipitation, immunofluorescence, and immunoblotting.
• Conducted electron and coherent anti-Stokes Raman scattering (CARS) microscopy.

Main Results:

• Observed Golgi and ER proliferations with protein aggregate buildup, affecting mitochondrial and cytoskeletal proteins.
• Proteomic profiling identified 120 vulnerable proteins in diseased muscle, revealing broader pathophysiology.
• Found alterations in DGC components and ubiquitination of other sarcolemmal proteins, while α-dystroglycan glycosylation remained unchanged.

Conclusions:

• p.P104L caveolinopathy is an ER-Golgi disorder causing impaired protein processing and aggregate formation.
• Pathology affects proteins vital for mitochondrial function, cytoskeleton, ECM, and sarcolemmal integrity.
• Findings suggest therapeutic strategies targeting protein folding capacity for caveolinopathy patients.