Does Myostatin Induce Insulin Resistance?

Bonala et al. (1) report that high glucose or fat increases myostatin protein expression in muscle and surprisingly liver (cells and tissue) and that myostatin induces insulin resistance. Their myostatin antiserum used for Western blotting and possibly ELISAs (not discussed) recognizes a reported 26-kDa protein under reducing conditions despite a predicted and empirically determined 12.5-kDa mass (2, 3). This group previously reported that the antiserum recognizes the same 26-kDa protein in mstn^−/− muscle extracts (4). Zimmers et al. (3) also identified this protein in wild-type and mstn^−/− mice, although their antiserum detected only a 12.5-kDa band in wild-type mice. Moreover, several studies have demonstrated the lack of myostatin mRNA in liver. These findings together suggest that Bonala et al. (1) did not quantify myostatin as their antiserum appears to cross-react with an unknown protein. There is also concern with their use of recombinant myostatin made in bacteria, which cannot form the critical disulfide necessary for myostatin maturation. These recombinants may function as dominant negatives and were reported to inhibit C2C12 proliferation whereas different sources of recombinant myostatin generated in eukaryotes stimulate it (5). In fact, concentrations used by Bonala et al. (1) were supraphysiological, 100-fold higher than the functional concentrations of recombinant myostatin made in eukaryotes, which greatly exceeds the nanomolar affinity range of ActRIIb. This use of highly questionable reagents in turn questions many of the authors' conclusions. It also adds confusion to the field, and unless the reagents can be finally validated, their use should be discontinued.