Supraphysiological activation of TAK1 in skeletal muscle stimulates translational machinery – protein synthesis and myofiber growth


In the gym, you are not just pumping iron, you are oxygenating muscle cells which keeps those muscles healthy, strong and growing—a process called hypertrophy, or an increase in muscle mass due to an increase in muscle cell size. Conversely, under the covers, lounging, your muscles may begin to atrophy, or shrink.

Scientists understand that a few signaling proteins are activated in various conditions of muscle atrophy and hypertrophy, but they have been stumped about the role and mechanisms by which TAK1, a protein that regulates innate immunity and the proinflammatory signaling pathways, regulates skeletal muscle mass, until University of Houston researchers began exploring.

“We demonstrate that supraphysiological activation of TAK1 in skeletal muscle stimulates translational machinery, protein synthesis and myofiber growth,” reports Ashok Kumar, UH College of Pharmacy Else and Philip Hargrove Endowed Professor and chair, Department of Pharmacological and Pharmaceutical Sciences, in Nature Communications.

Using genetic approaches, Kumar and research assistant professor Anirban Roy demonstrated that TAK1 is indispensable for maintaining healthy neuromuscular junctions, which are involved in transmitting nerve impulses to skeletal muscle and allow muscle contractions.

“Our findings demonstrate that targeted inactivation of TAK1 causes derangement of neuromuscular junctions and severe muscle wasting, very similar to muscle wasting observed during nerve damage, aging and cancer cachexia. We have also identified a novel interplay between TAK1 and BMP (Bone Morphogenetic Protein) signaling pathway that promotes muscle growth,” said Roy.

Nutrients, growth hormones and weight training all result in an increase in skeletal muscle mass in healthy individuals. Conversely, many disease conditions often lead to a loss in lean muscle mass. Understanding the mechanisms regulating protein and organelle content is highly important to identify drug targets for various muscle wasting conditions and neuromuscular disorders.

The team also reports that activation of TAK1 in skeletal muscle beyond normal levels can prevent excessive muscle loss due to nerve damage. Loss of muscle mass has a devastating impact on standard-of-care treatment during aging and terminal illnesses, such as cancer, COPD, kidney failure and in many genetic neuromuscular diseases.

“Recognizing the impact of TAK1 signaling in supporting muscle growth, our research opens up new avenues to develop therapies for these and many other pathological conditions and improve quality of life,” said Roy.

Future studies will investigate whether the activation of TAK1 using small molecules is sufficient to promote muscle growth and prevent atrophy in the elderly and various disease states.

Loss of skeletal muscle mass and strength leads to severe consequences, resulting in permanent disability and mortality in the elderly and in settings of functional denervation, as well as in many chronic disease states (1). Skeletal muscle mass is governed by a fine balance between the rate of protein synthesis and degradation (2). In addition, mitochondria play a pivotal role in the maintenance of skeletal muscle mass and metabolic function (3). Perturbation in mitochondrial dynamics and function is responsible for skeletal muscle wasting in multiple pathophysiological conditions (4, 5).

Skeletal muscle mass is regulated by a number of signaling pathways. For example, the activation of the Akt/mTOR signaling pathway induces skeletal muscle growth (6, 7) and prevents muscle protein degradation (6–9). While promoting mitochondrial biogenesis and metabolic adaptation, activation of AMPK inhibits protein synthesis in skeletal muscle through suppressing mTOR activity (10, 11). AMPK also induces protein degradation through stimulating the ubiquitin-proteasome system (UPS) and autophagy (12–14).

Several inflammatory cytokines, microbial products, and tumor-derived factors induce muscle wasting through the activation of canonical NF-κB and p38 MAPK signaling pathways (15–17). Furthermore, TGF-β and its closely related family members, myostatin, activin, and growth and differentiation factor 11 (GDF11), cause muscle wasting through the activation of Smad2/3 transcription factors (2, 18). However, the proximal signaling events that regulate the activation of these pathways in skeletal muscle remain less understood.

TGF-β–activated kinase 1 (TAK1, also known as MAPK3K7) is a member of the MEK kinase (MAP3K) family that mediates context-dependent activation of distinct signaling pathways. TAK1 forms a complex with TAK1-binding protein 1 (TAB1) and with either TAB2 or TAB3 (19).

Upon cytokine stimulation, the TAK1 complex is activated by K63-linked polyubiquitination reactions catalyzed by the E2 enzyme complex Uev1A-Ubc13 and the RING finger E3 ligases TRAF2 or TRAF6. The specific interaction of the K63-Ub chains with the C-terminal domains of TAB2 and TAB3 induces a conformational change that leads to the autophosphorylation of TAK1 (20).

Activated TAK1 phosphorylates the specific MAPK kinases (MKK), which leads to the activation of JNK1/2 and p38 MAPK (21). TAK1 also phosphorylates inhibitor of κ B (IκB) kinase β (IKKβ), leading to the phosphorylation and degradation of IκB proteins, which results in the activation of NF-κB transcription factor (22, 23). It has been consistently observed that NF-κB is a negative regulator of skeletal muscle mass and function (2, 15, 16). However, the physiological role of TAK1 in the regulation of skeletal muscle remains unknown.

Because conventional Tak1-null mice are embryonically lethal (24, 25), for this study, we generated inducible skeletal muscle–specific Tak1-null mice. Our results demonstrate that inducible inactivation of TAK1 causes severe muscle wasting and kyphosis in mice without having any effect on the survival of myofibers.

Deletion of TAK1 inhibits the rate of protein synthesis and stimulates the activation of proteolytic systems in skeletal muscle. Furthermore, targeted ablation of TAK1 induces oxidative stress and leads to the accumulation of dysfunctional mitochondria in the skeletal muscle of adult mice. Finally, we found that TAK1 is essential for overload-induced skeletal muscle hypertrophy in adult mice. Altogether, our study demonstrates a previously unrecognized role of TAK1 in the regulation of skeletal muscle mass and health.

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More information: Anirban Roy et al, Supraphysiological activation of TAK1 promotes skeletal muscle growth and mitigates neurogenic atrophy, Nature Communications (2022). DOI: 10.1038/s41467-022-29752-0


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