Skeletal muscle atrophy results in loss of strength and an increased risk of mortality. We found that lysophosphatidic acid, which activates a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, stimulated skeletal muscle hypertrophy through activation of Gα(i2). Expression of a constitutively active mutant of Gα(i2) stimulated myotube growth and differentiation, effects that required the transcription factor NFAT (nuclear factor of activated T cells) and protein kinase C. In addition, expression of the constitutively active Gα(i2) mutant inhibited atrophy caused by the cachectic cytokine TNFα (tumor necrosis factor-α) by blocking an increase in the abundance of the mRNA encoding the E3 ubiquitin ligase MuRF1 (muscle ring finger 1). Gα(i2) activation also enhanced muscle regeneration and caused a switch to oxidative fibers. Our study thus identifies a pathway that promotes skeletal muscle hypertrophy and differentiation and demonstrates that Gα(i2)-induced signaling can act as a counterbalance to MuRF1-mediated atrophy, indicating that receptors that act through Gα(i2) might represent potential targets for preventing skeletal muscle wasting.

e Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.

eWe have previously shown that activation of G␣i2, an ␣ subunit of the heterotrimeric G protein complex, induces skeletal muscle hypertrophy and myoblast differentiation. To determine whether G␣i2 is required for skeletal muscle growth or regeneration, G␣i2-null mice were analyzed. G␣i2 knockout mice display decreased lean body mass, reduced muscle size, and impaired skeletal muscle regeneration after cardiotoxin-induced injury. Short hairpin RNA (shRNA)-mediated knockdown of G␣i2 in satellite cells (SCs) leads to defective satellite cell proliferation, fusion, and differentiation ex vivo. The impaired differentiation is consistent with the observation that the myogenic regulatory factors MyoD and Myf5 are downregulated upon knockdown of G␣i2. Interestingly, the expression of microRNA 1 (miR-1), miR-27b, and miR-206, three microRNAs that have been shown to regulate SC proliferation and differentiation, is increased by a constitutively active mutant of G␣i2 [G␣i2(Q205L)] and counterregulated by G␣i2 knockdown. As for the mechanism, this study demonstrates that G␣i2(Q205L) regulates satellite cell differentiation into myotubes in a protein kinase C (PKC)-and histone deacetylase (HDAC)-dependent manner. Heterotrimeric G proteins are intracellular proteins and transduce external signals from a variety of cell surface receptors to intracellular effectors (1). G proteins are classified according to their ␣ subunits into four subfamilies: G␣s, G␣i/o, G␣q/11, and G␣ 12/13 (1). The G␣i subfamily is encoded by three genes, GNAI1, GNAI2, and GNAI3, and was originally identified by its ability to inhibit adenylyl cyclase activity. All three G␣i isoforms have been deleted by gene targeting in mice, and the resulting phenotypes indicate that they have both overlapping and distinct functions. Ablation of G␣i1 in mice modulates adenylyl cyclase activity in the hippocampus and impairs memory formation (2). G␣i2-deficient mice display growth retardation, develop ulcerative colitis (3), and present defects of the parasympathetic heart rate (4), while G␣i3 has been shown to modulate insulin regulation of autophagy in hepatocytes (5) and to be required for normal patterning of the axial skeleton (6) and for cytoskeleton-dependent control of cilium migration as an important step in establishing planar cell polarity in cochlear cells (7). However, the requirement for G␣i isoforms in skeletal muscle growth and regeneration has not been determined.Mammalian skeletal muscle has the ability to regenerate and repair in response to exercise or injury. Regeneration of skeletal muscle is mainly executed by satellite cells (SCs) (8). SCs are a population of muscle stem cells that reside between the sarcolemma and the basal lamina. In neonatal muscle, growth is mainly achieved by addition of myoblasts derived from SCs to existing myofibers (9, 10). In the adult muscle, SCs-quiescent under normal physiological conditions-are activated in response to trauma and are able to self-renew, proliferate, and differentiate to fuse to damaged fibers or fo...

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