1. In higher eukaryotes, metabolism and immunity are tightly coupled. However, whereas in evolutionary terms a compromised immune response due to undernourishment has been the predominant problem, the inflammatory response to obesity and other lifestyle-associated diseases has increased in relevance in Western societies in the past 100 years.
2. Traditionally, fat tissue has been considered as the major source of pro-inflammatory secreted factors in these pathologies. However, in recent years the contribution of other tissues to disease-causing chronic inflammation has been increasingly appreciated.
3. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is one of the key regulatory factors in active skeletal muscle. Aberrant expression of PGC-1α in inactive muscle fibres could be linked to a sedentary lifestyle, persistent systemic inflammation and a higher risk for many chronic diseases. Accordingly, modulation of PGC-1α activity in skeletal muscle may have a broad range of therapeutic effects. Here, recent advances in the understanding of the role of muscle PGC-1α in health and disease are reviewed.