Can low testosterone contribute to fatigue, reduced exercise tolerance, and difficulty building muscle?

Low testosterone in aging men disrupts essential physiological pathways, directly impacting physical stamina, energy regulation, and skeletal muscle maintenance.

Mechanistic pathways of androgen deficiency

• Anabolic signaling impairment: Low testosterone blunts androgen receptor (AR) signaling in skeletal muscle, downregulating the crucial Akt/mTORC1 pathway required for protein synthesis and muscle mass maintenance.
• Myogenic and catabolic alterations: Impaired AR signaling reduces the expression of myogenic factors like MYOD1 and satellite-cell stimulators such as FGF2, while upregulating catabolic markers like myostatin, which promotes muscle atrophy.
• Metabolic and neuromuscular disruption: Deficient signaling compromises muscle glycolytic capacity, neuromuscular excitability, and metabolic gene programs, shifting muscle recruitment toward more easily fatigued fibers.

Clinical and physical outcomes

• Fatigue and exercise intolerance: These metabolic and transcriptional alterations manifest clinically as chronic physical fatigue, reduced cardiorespiratory performance, compromised oxygen consumption, and diminished overall exercise capacity.
• Impaired muscle accretion: The blunting of anabolic cascades and downregulation of protein synthesis create significant barriers to building muscle, accelerating phenotypes that resemble sarcopenia.

Bottom line

• Low testosterone impairs physical function and muscle growth by reducing AR-dependent Akt/mTORC1 signaling, neuromuscular excitability, and metabolic gene expression, resulting in systemic fatigue, poor exercise tolerance, and anabolic resistance.