Genetic compensation for sarcoglycan loss by integrin α7β1 in muscle

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Abstract
Disruption of the sarcoglycan complex leads to muscle membrane instability and muscular dystrophy in humans and mice. Through the dystrophin glycoprotein complex, sarcoglycan participates in connecting the internal cytoskeleton to the membrane and the extracellular matrix. Integrin α7β1 is also a transmembrane protein of skeletal and cardiac muscle that similarly links the cytoskeleton to the extracellular matrix. Mice lacking integrin α7 develop mild muscle degeneration, while sarcoglycan mutant mice display overt muscle degeneration and muscular dystrophy. In sarcoglycan-deficient muscle, integrin α7 protein was upregulated at the plasma membrane. To ascertain whether integrin α7 upregulation compensates for the loss of the transmembrane sarcoglycan linkage in sarcoglycan-deficient muscle, we generated mice lacking both integrin α7 and γ-sarcoglycan (gxi). These double-mutant gxi mice exhibit profound, rapid muscle degeneration leading to death before one month of age consistent with a weakened cellular attachment to the extracellular matrix. The regenerative capacity of gxi muscle was intact with increased embryonic myosin heavy chain expression, myofiber central nucleation and normal in vivo myoblast differentiation. Therefore, upregulation of integrin α7β1 compensates as a transmembrane muscle cell attachment for sarcoglycan consistent with overlapping roles for sarcoglycan and integrins in mediating cytoskeletal-membrane-extracellular matrix interaction.