Muscle Wasting Diseases: Novel Targets and Treatments

Abstract

Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular pathologies, current treatments are mostly targeted on non-muscle tissues. In recent years, a renewed focus on skeletal muscle has led to the discovery of various novel drug targets and the design of new pharmacological approaches. This review provides an overview of the current knowledge of the key mechanisms involved in muscle wasting conditions and novel pharmacological avenues that could ameliorate muscle diseases.

Keywords: atrophy; exon skipping; gene therapy; muscle wasting; muscular dystrophy; proteostasis.

Figure 1. Signaling pathways involved in secondary muscle wasting and potential drugs to reduce loss of muscle mass.

Several classes of drugs are tested in clinical trials aimed at either inhibiting catabolic signaling (drug name red) and thereby reducing protein degradation (orange), or stimulating anabolic pathways (drug name green) and thereby increasing protein synthesis (blue). Activation via IGF-1, but also other upstream signals such as GH, androgens or β2-agonist, stimulate the PI3K – Akt – mTOR pathway and, as a consequence, protein synthesis is increased. In addition, Akt suppresses protein degradation by phosphorylating FoxO and thereby reducing its transcriptional activity. Several catabolic pathways do not only contribute to muscle atrophy by increasing the expression of E3 ligases MAFbx and MuRF1 via the transcription factors FoxO, TFEB or NF-κB, which all stimulate protein degradation, but also by inhibiting PI3K – Akt signaling and thereby reduce protein synthesis. MSTN is a major negative regulator of muscle mass by inhibiting Akt signaling. The multi-factorial nature of secondary muscle wasting and the different signaling pathways involved in muscle atrophy aggravates the development of effective drugs. Abbreviations not mentioned in the text: T = testosterone; GC = glucocorticoid